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How does UV light damage the DNA when the chromosomes are deep inside the cell?

How does UV light damage the DNA when the chromosomes are deep inside the cell?


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When UV light falls on the skin it has to go through the cell membrane and the nuclear membrane to reach the chromosomes. So it looks like that the DNA is protected but it probably isn't. Won't membranes be damaged first and the so that the cell dies before the DNA is affected and is replicating wrongly (if it is damaged too)? Or is DNA just really much more vulnerable than cell membrane?


UV Rays kill the cells by damaging the DNA. UV lights do not disrupt the cell membrane. If a cell is exposed to UV light, it creates THYMINE dimers (bond). Thymine dimers are the actual disruption in the kinks of DNA. UV exposure to skin is proportional to the cell damage.

P53 is a gene product which takes care of fixing cell damage. However it has a tolerance. If the damage is less, P53 sends damage repair machinery. If it's non-fixable, then P53 directs the cell to programmed death.

More UV exposure, more thymine dimers causing more cells to die (cell death). If the damage is not extensive, then that may cause cancerous cells (Result of cell damage).


When UV light is on your skin it has to go through the cell membrane and to the membrane of the core. So it looks like that the DNA is protected.

I don't understand what you mean by membrane of the core (perhaps nuclear membrane) but yes there is cell membrane and other cytosolic components. You should, however note that not all cells are spherical; some cells like skin cells are flat and along the thickness axis the DNA is much "less buried".

However, UV light does get attenuated by different cellular components. Melanin (which gives the skin a tan), for instance, absorbs UV and protects the DNA.

In spite of all this UV can reach the DNA. Furthermore, DNA (basically the bases) can absorb UV because of the nature of their chemical structure. After absorbing UV they reach an excited state and can become reactive. Reactions such as pyrimidine dimerization happens because of UV absorption. Note that this kind of an effect is elicited only by high energy UV (200-300 nm) (Durbeej and Eriksson, 2002; Svobodová et al., 2012).

Low energy UV (UVA) does not damage the DNA directly but can do that indirectly by generating free radicals. These free radicals are generated when other cellular components absorb UV and become reactive. Lipids are also affected by UVA and UVB; lipid peroxidation happens in the presence of UV and these peroxides are a source of free radicals (Morliere et al., 1995). So, the membrane is indeed "damaged".

It is also interesting to note that UVA is the most available to the skin cells because UVC and UVB are filtered to a great extent by the ozone layer and also scattered/absorbed by skin components (What is the relationship between UV wavelength and penetration depth into human skin?).

To summarize, DNA is more vulnerable to certain UV ranges but the damage frequently happens indirectly by other free radicals generated in the cytosol.


How Sunscreen Protects Your Skin’s DNA

Not so long ago, people like my Aunt Muriel thought of sunburn as a necessary evil on the way to a “good base tan.” She used to slather on the baby oil while using a large reflector to bake away. Aunt Muriel’s mantra when the inevitable burn and peel appeared: Beauty has its price.

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Was she ever right about that price – but it was a lot higher than any of us at the time recognized. What sun addicts didn’t know then was that we were setting our skin up for damage to its structural proteins and DNA. Hello, wrinkles, liver spots and cancers. No matter where your complexion falls on the Fitzpatrick Skin Type scale, ultraviolet radiation (UV) from the sun or tanning beds will damage your skin.

Today, recognition of the risks posed by UV rays has motivated scientists, myself included, to study what’s going on in our cells when they’re in the sun – and devise modern ways to ward off that damage.

UV light that affects our skin has a shorter wavelength than the parts of the electromagnetic spectrum we can see. (Inductiveload, NASA, CC BY-SA)

Sunlight is composed of packets of energy called photons. The visible colors we can see by eye are relatively harmless to our skin it’s the sun’s ultraviolet (UV) light photons that can cause skin damage. UV light can be broken down into two categories: UVA (in the wavelength range 320-400 nanometers) and UVB (in the wavelength range 280� nm).

Our skin contains molecules that are perfectly structured to absorb the energy of UVA and UVB photons. This puts the molecule into an energetically excited state. And as the saying goes, what goes up must come down. In order to release their acquired energy, these molecules undergo chemical reactions – and in the skin that means there are biological consequences.

Interestingly, some of these effects used to be considered helpful adaptations – though we now recognize them as forms of damage. Tanning is due to the production of extra melanin pigment induced by UVA rays. Exposure to the sun also turns on the skin’s natural antioxidant network, which deactivates highly destructive reactive oxygen species (ROS) and free radicals if left unchecked, these can cause cellular damage and oxidative stress within the skin.

We also know that UVA light penetrates deeper into the skin than UVB, destroying a structural protein called collagen. As collagen degrades, our skin loses its elasticity and smoothness, leading to wrinkles. UVA is responsible for many of the visible signs of aging, while UVB light is considered the primary source of sunburn. Think “A” for aging and “B” for burning.

DNA itself can absorb both UVA and UVB rays, causing mutations which, if unrepaired, can lead to non-melanoma (basal cell carcinoma, squamous cell carcinoma) or melanoma skin cancers. Other skin molecules pass absorbed UV energy on to those highly reactive ROS and free radicals. The resulting oxidative stress can overload the skin’s built-in antioxidant network and cause cellular damage. ROS can react with DNA, forming mutations, and with collagen, leading to wrinkles. They can also interrupt cell signaling pathways and gene expression.

The end result of all of these photoreactions is photodamage that accumulates over the course of a lifetime from repeated exposure. And – this cannot be emphasized enough – this applies to all skin types, from Type I (like Nicole Kidman) to Type VI (like Jennifer Hudson). Regardless of how much melanin we have in our skin, we can develop UV-induced skin cancers and we will all eventually see the signs of photo-induced aging in the mirror.

The good news, of course, is that the risk of skin cancer and the visible signs of aging can be minimized by preventing overexposure to UV radiation. When you can’t avoid the sun altogether, today’s sunscreens have got your back (and all the rest of your skin too).

Sunscreens employ UV filters: molecules specifically designed to help reduce the amount of UV rays that reach through the skin surface. A film of these molecules forms a protective barrier either absorbing (chemical filters) or reflecting (physical blockers) UV photons before they can be absorbed by our DNA and other reactive molecules deeper in the skin.

In the United States, the Food and Drug Administration regulates sunscreens as drugs. Because we were historically most concerned with protecting against sunburn,㺎 molecules that block sunburn-inducing UVB rays are approved for use. That we have just two UVA-blocking molecules available in the United States – avobenzone, a chemical filter and zinc oxide, a physical blocker – is a testament to our more recent understanding that UVA causes trouble, not just tans.

The FDA also has enacted strict labeling requirements – most obviously about SPF (sun protection factor). On labels since 1971, SPF represents the relative time it takes for an individual to get sunburned by UVB radiation. For example, if it takes 10 minutes typically to burn, then, if used correctly, an SPF 30 sunscreen should provide 30 times that – 300 minutes of protection before sunburn.

“Used correctly” is the key phrase. Research shows that it takes about one ounce, or basically a shot glass-sized amount of sunscreen, to cover the exposed areas of the average adult body, and a nickel-sized amount for the face and neck (more or less, depending on your body size). The majority of people apply between a quarter to a half of the recommended amounts, placing their skin at risk for sunburn and photodamage.

In addition, sunscreen efficacy decreases in the water or with sweating. To help consumers, FDA now requires sunscreens labeled “water-resistant” or “very water-resistant” to last up to 40 minutes or 80 minutes, respectively, in the water, and the American Academy of Dermatology and other medical professional groups recommend reapplication immediately after any water sports. The general rule of thumb is to reapply about every two hours and certainly after water sports or sweating.

In the U.S., the FDA regulates sunscreens available to consumers. (Sheila Fitzgerald via Shutterstock.com)

To get high SPF values, multiple UVB UV filters are combined into a formulation based upon safety standards set by the FDA. However, the SPF doesn’t account for UVA protection. For a sunscreen to make a claim as having UVA and UVB protection and be labeled “Broad Spectrum,” it must pass FDA’s Broad Spectrum Test, where the sunscreen is hit with a large dose of UVB and UVA light before its effectiveness is tested.

This pre-irradiation step was established in FDA’s 2012 sunscreen labeling rules and acknowledges something significant about UV-filters: some can be photolabile, meaning they can degrade under UV irradiation. The most famous example may be PABA. This UVB-absorbing molecule is rarely used in sunscreens today because it forms photoproducts that elicit an allergic reaction in some people.

But the Broad Spectrum Test really came into effect only once the UVA-absorbing molecule avobenzone came onto the market. Avobenzone can interact with octinoxate, a strong and widely used UVB absorber, in a way that makes avobenzone less effective against UVA photons. The UVB filter octocrylene, on the other hand, helps stabilize avobenzone so it lasts longer in its UVA-absorbing form. Additionally, you may notice on some sunscreen labels the molecule ethylhexyl methoxycrylene. It helps stabilize avobenzone even in the presence of octinoxate, and provides us with longer-lasting protection against UVA rays.

Next up in sunscreen innovation is the broadening of their mission. Because even the highest SPF sunscreens don’t block 100 percent of UV rays, the addition of antioxidants can supply a second line of protection when the skin’s natural antioxidant defenses are overloaded. Some antioxidant ingredients my colleagues and I have worked with include tocopheral acetate (Vitamin E), sodium ascorbyl phosophate (Vitamin C), and DESM. And sunscreen researchers are beginning to investigate if the absorption of other colors of light, like infrared, by skin molecules has a role to play in photodamage.

As research continues, one thing we know for certain is that protecting our DNA from UV damage, for people of every color, is synonymous with preventing skin cancers. The Skin Cancer Foundation, American Cancer Society and the American Academy of Dermatology all stress that research shows regular use of an SPF 15 or higher sunscreen prevents sunburn and reduces the risk of non-melanoma cancers by 40 percent and melanoma by 50 percent.

We can still enjoy being in the sun. Unlike my Aunt Muriel and us kids in the 1980s, we just need to use the resources available to us, from long sleeves to shade to sunscreens, in order to protect the molecules in our skin, especially our DNA, from UV damage.


This article was originally published on The Conversation.

Kerry Hanson, Research Chemist, University of California, Riverside


Introduction

Early embryogenesis in many organisms, including Xenopus laevis, Drosophila melanogaster, and Caenorhabditis elegans, is characterized by rapid progression through the cell cycle (for review see O'Farrell et al., 2004). Features of early embryonic cell cycles that distinguish them from somatic cycles include cell division in the absence of cell growth and a lack of Gap phases. Another important difference between somatic and embryonic cell cycles concerns the utilization of S phase checkpoint pathways. In somatic cells, the S phase checkpoint senses DNA damage and responds by delaying progression into mitosis (for reviews see Bartek et al., 2004 Sancar et al., 2004). The protein kinases ATR and Chk1 are central to S phase checkpoint signaling. DNA damage causes replication fork stalling, which in turn activates ATR and promotes the ATR-directed phosphorylation of Chk1. Activated Chk1 delays cell cycle progression through attenuation of core cell cycle regulators such as the Cdc25 protein phosphatase. Thus, in somatic cells, a major function of the ATR checkpoint is to delay cell cycle progression in response to DNA damage until replication can finish.

In embryonic cells, the ATR checkpoint is activated by endogenous, developmentally programmed cues. The nature of these signals is not defined, but it is clear that developmental activation of the checkpoint is important for regulating the timing of cell division during early embryogenesis. Two examples highlight this importance. In D. melanogaster, the mei-41 (ATR) and grapes (Chk1) genes affect a developmentally programmed slowing of the cell cycle that occurs at the midblastula transition (Sibon et al., 1997, 1999 Su et al., 1999 Yu et al., 2000). Fly embryos perform 13 rounds of rapid and synchronous cell division before the midblastula transition. After cycle 13, the mei41/grapes checkpoint is activated by an endogenous signal, and this slows the cell cycle down. Slowing of the cell cycle in turn allows for zygotic transcription to begin, and the control of cell division is thereby transferred from maternal to zygotic regulators. In mei-41 or grapes mutants, the cell cycle does not slow down, zygotic control of the cell cycle does not happen on schedule, and the embryo dies. Therefore, in D. melanogaster, the checkpoint plays an important role in remodeling the cell cycle so that zygotic transcription can begin on schedule.

Another example of DNA damage–independent utilization of the ATR checkpoint is found in C. elegans. The one-cell embryo, or P0 cell, divides asymmetrically to produce the smaller (P1) and the larger (AB) daughter cells. The next round of cell division is asynchronous: AB divides first, followed by P1 about 2 min later. This 2-min delay is controlled in part through differential activation of the S phase checkpoint in the P1 cell (Brauchle et al., 2003). Developmental checkpoint activation in the early embryo requires the C. elegans homologues of ATR (atl-1) and Chk1 (chk-1). Checkpoint-mediated asynchrony in cell division is extremely important to embryonic patterning in C. elegans. When asynchrony is reduced, through loss of chk-1, the germ line fails to develop and the animal is sterilized (Brauchle et al., 2003 Kalogeropoulos et al., 2004). Extending the asynchrony also has deleterious consequences. Hypomorphic mutations in div-1, a gene encoding DNA polymerase α, cause replication problems that result in inappropriate activation of the chk-1 pathway (Encalada et al., 2000 Brauchle et al., 2003). The div-1–mediated activation of chk-1 extends the asynchrony in cell division, and this results in mislocalization of developmental regulators, embryonic patterning defects, and lethality (Encalada et al., 2000).

From these examples it is clear that, although checkpoint activation is important for development, it must only occur in response to developmental signals and not in response to unscheduled events such as replication problems. A common source of replication problems in wild-type cells is DNA damage, and thus it would seem that early embryogenesis in C. elegans would be particularly sensitive to DNA damage because of the deleterious consequences of unscheduled checkpoint activation. Paradoxically, this is not so, as previous work has shown that wild-type embryos are resistant to relatively high amounts of both UV light and the alkylating agent methyl methanesulphonate (MMS Hartman and Herman, 1982 Holway et al., 2005), two DNA-damaging agents that are known to cause replication problems and subsequent checkpoint activation (Lupardus et al., 2002 Stokes et al., 2002 Tercero et al., 2003). We resolve this paradox by showing that the checkpoint is actively silenced during the DNA damage response in early embryos. We go on to define genetic requirements and the basis for checkpoint silencing. Our results identify a novel developmental mechanism that ensures that cell cycle progression is not attenuated by DNA damage, thus providing embryos with a chance of survival even when their chromosomes are heavily damaged.


Results

Inactivation of human coronaviruses after exposure to 222 nm light in aerosols infectivity assay

We used a standard approach to measure viral inactivation, assaying coronavirus infectivity in human host cells (normal lung cells), in this case after exposure in aerosols to different doses of far-UVC light. We quantified virus infectivity with the 50% tissue culture infectious dose TCID50 assay 28 , and estimated the corresponding plaque forming units (PFU)/ml using the conversion PFU/ml = 0.7 TCID50 29 . Figure 1 shows the fractional survival of aerosolized coronaviruses HCoV-229E and HCoV-OC43 expressed as PFUUV/PFUcontrols as a function of the incident 222-nm dose. Robust linear regression (Table 1) using iterated reweighted least squares 30 indicated that the survival of both genera alpha and beta is consistent with a classical exponential UV disinfection model (R 2 = 0.86 for HCoV-229E and R 2 = 0.78 for HCoV-OC43). For the alpha coronavirus HCoV-229E, the inactivation rate constant (susceptibility rate) was k = 4.1 cm 2 /mJ (95% confidence intervals (C.I.) 2.5–4.8) which corresponds to an inactivation cross-section (or the dose required to kill 90% of the exposed viruses) of D90 = 0.56 mJ/cm 2 . Similarly, the susceptibility rate for the beta coronavirus HCoV-OC43 was k = 5.9 cm 2 /mJ (95% C.I. 3.8–7.1) which corresponds to an inactivation cross section of D90 = 0.39 mJ/cm 2 .

Coronavirus survival as function of the dose of far-UVC light. Fractional survival, PFUUV / PFUcontrols, is plotted as a function of the 222-nm far-UVC dose. The results are reported as the estimate plaque forming units (PFU)/ml using the conversion PFU/ml = 0.7 TCID50 29 by applying the Poisson distribution. Values are reported as mean ± SEM from multiple experiments (n = 3 alpha HCoV-229E and n = 4 for beta HCoV-OC43) the lines represent the best-fit regressions to equation (1) (see text and Table 1).

Viral integration assay

We investigated integration of the coronavirus in human lung host cells, again after exposure in aerosols to different doses of far-UVC light. Figures 2 and 3 show representative fluorescent 10x images of human lung cells MRC-5 and WI-38 incubated, respectively, with HCoV-229E (Fig. 2) and HCoV-OC43 (Fig. 3), which had been exposed in aerosolized form to different far-UVC doses. The viral solution was collected from the BioSampler after running through the aerosol chamber while being exposed to 0, 0.5, 1 or 2 mJ/cm 2 of 222-nm light. Cells were incubated with the exposed virus for one hour, the medium was replaced with fresh infection medium, and immunofluorescence was performed 24 hours later. We assessed the human cell lines for expression of the viral spike glycoprotein, whose functional subunit S2 is highly conserved among coronaviruses 31,32 . In Figs. 2 and 3, green fluorescence (Alexa Fluor-488 used as secondary antibody against anti-human coronavirus spike glycoprotein antibody) qualitatively indicates infection of cells with live virus, while the nuclei were counterstained with DAPI appearing as blue fluorescence. For both alpha HCoV-229E and beta HCoV-OC43, exposure to 222-nm light reduced the expression of the viral spike glycoprotein as indicated by a reduction in green fluorescence.

Infection of human lung cells from irradiated aerosolized alpha HCoV-229E as function of dose of far-UVC light. Representative fluorescent images of MRC-5 normal human lung fibroblasts infected with human alphacoronavirus 229E exposed in aerosolized form. The viral solution was collected from the BioSampler after running through the aerosol chamber while being exposed to (a) 0, (b) 0.5, (c) 1 or (d) 2 mJ/cm 2 of 222-nm light. Green fluorescence qualitatively indicates infected cells (Green = Alexa Fluor-488 used as secondary antibody against anti-human coronavirus spike glycoprotein antibody Blue = nuclear stain DAPI). Images were acquired with a 10× objective the scale bar applies to all the panels in the figure.

Infection of human lung cells from irradiated aerosolized beta HCoV-OC43 as function of dose of far-UVC light. Representative fluorescent images of WI-38 normal human lung fibroblasts infected with human betacoronavirus OC43 exposed in aerosolized form. The viral solution was collected from the BioSampler after running through the aerosol chamber while being exposed to (a) 0, (b) 0.5, (c) 1 or (d) 2 mJ/cm 2 of 222-nm light. Green fluorescence qualitatively indicates infected cells (Green = Alexa Fluor-488 used as secondary antibody against anti-human coronavirus spike glycoprotein antibody Blue = nuclear stain DAPI). Images were acquired with a 10× objective the scale bar applies to all the panels in the figure.


How does UV light damage the DNA when the chromosomes are deep inside the cell? - Biology

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cell cycle, checkpoints and cancer

Laura Carrassa

Laboratory of Molecular Pharmacology Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri Via La Masa 19, 20156 Milan, Italy

Maintenance of genomic integrity is a pre-requisite for a safe and long lasting life and prevents development of diseases associated with genomic instability such as cancer. DNA is constantly subjected and damaged by a large variety of chemical and physical agents, thus cells had to set up a number of surveillance mechanisms that constantly monitor the DNA integrity and the cell cycle progression and in the presence of any type of DNA damage activate pathways that lead to cell cycle checkpoints, DNA repair, apoptosis and transcription. In recent years checkpoint pathways have been elucidated as an integral part of the DNA damage response and in fact dysfunctions or mutations of these pathways are important in the pathogenesis of malignant tumors. Understanding the molecular mechanisms regulating the cell cycle progression and checkpoints and how these processes are altered in malignant cells may be crucial to better define the events behind such a complex and devastating desease like cancer (Poehlmann and Roessner, 2010 Vermeulen et al., 2003 Aarts et al., 2013 Kastan and Bartek, 2004).

Cell cycle regulation

The cell cycle is a succession of very well organized molecular events that give the ability to the cell to produce the exact itself's copy. The DNA replication and the segregation of replicated chromosomes are the main events of the cell cycle. The DNA replication occurs during the so called S phase (synthetic phase) which is preceded by the DNA synthesis preparatory phase (Gap1 or G1 phase), whereas the nuclear division occurs in mitosis (M phase) and is preceded by the mitotic preparatory phase (gap 2 or G2 phase). The G1, S and G2 phases represent the interphase of a proliferating cell and constitute the time lapse between two consecutive mitoses. The differentiated cells that do not proliferate enter in the so called G0 phase which is a steady state phase or resting phase (Vermeulen et al., 2003).

The progression of a cell through the cell cycle is strictly regulated by key regulatory proteins called CDK (cyclin dependent kinase) which avoid the initiation of a cell cycle phase before the completion of the preceding one. The cdks are a family of serine/threonine protein kinases that are activated at specific points of the cell cycle consisting of a catalytic subunit with a low intrinsic enzymatic activity and of a fundamental positive regulatory subunit called cyclin (Pavletich, 1999). Cyclin protein levels rise and fall during the cell cycle, activating the corresponding cdk, whereas the cdk protein levels are kept constant throughout the cell cycle. Once the complex cdk-cyclin is formed, it gets activated by the protein CAK (cdk activating protein) which phosphorylates the complex ensuring the subsequent phosphorylation of target gene products required for the progression of the cell through the cell cycle (Morgan, 1995). When quiescent cells are stimulated by mitogen signals, CDK4 and CDK6 are activated by association with D type cyclins. These above cited cdk-cyclin complexes are important for the progression through the G1 phase and the restriction point preparing the cell to the replicative phase by phosphorylating the oncosuppressor protein pRb which causes the activation of the E2F family transcription factors. The activation of CDK4 and CDK6 is followed by the subsequent activation of CDK2 by cyclin E and cyclin A, which in turn initiates DNA replication. As the DNA replication process finishes, the Cdk1/cyclin B complex is activated leading to mitosis (Vermeulen et al., 2003 Sherr and Roberts, 1999). Until the end of G2 phase, CDK1 is phos-phorylated at Thr14 and Tyr15 by the kinases WEE1 and MYT1, resulting in inhibition of cyclin B-CDK1 activity. Mitotic entry is ultimately initiated by depho-sphorylation of these residues by the CDC25 family of phosphatases, initiating a positive feedback loop that stimulates cyclin B-CDK1 activity and entry into mitosis (Lindqvist et al., 2009). The activation status of the cdk-cyclin complexes is also monitored by negative regulation of the ATP binding site by phosphorylation in specific residues and subsequent reactivation by specific phosphatases which dephosphorylate the same residues. Inhibitory proteins also contribute to negatively regulate the cdks by forming either binary complexes with cdks or ternary complexes with cyclin cdk dimers (figure 1). Three distinct families of these so called cyclin dependent kinase inhibitors (CKI) can be distinguished. The first one is called INK family and is composed by four members: p15, p16, p18 and p19. They mainly regulate the G1-S transition of the cell cycle targeting to CDK4 and CDK6 by binding the cdk subunit and causing a conformational change of the kinases which become inactive precluding the cyclin binding. The second family of inhibitors is the Cip/Kip family and consists of three members: p21 cip1 , p27 kip1 and p57 kip2 . The components of this group negatively regulate the cdk2/cyclinA and cdk2/cyclinE complexes whereas they positively regulate the cdk4/6 cyclinD complexes by facilitating and stabilizing the association of cyclin and CDKs. The final class of inhibitors is the pRb protein family which consists of two members: p107 and p130. These proteins, better known as transcriptional inhibitors, act as potent cyclin E/A-cdk2 inhibitors by binding both to cyclin and to cdk sites (Vermeulen et al., 2003 Cobrinik, 2005).

An additional level of cdk regulation is the control of nuclear import/export which can be easily exemplified by the cyclinB1-Cdk1 complex that is kept out of the nucleus through an active nuclear export until late G2, when the nuclear exporting signals are inactivated by phosphorylation ensuring nuclear accumulation. The regulation of the Cdk1-cyclinB1 complex via cytoplasmic sequestration together with the negative regulatory phosphorylation of Cdk1 prevents premature phosphorylation of mitotic targets and the entry in mitosis (Yang et al., 1998). Other examples are the CDK inactivating kinases Wee1 and Myt1 located respectively in the nucleus and Golgi complex protecting the cells from premature mitosis and the 14-3-3 group of proteins that regulate the intracellular trafficking of different proteins such as the phosphatase Cdc25C (Peng et al., 1997). The above mentioned events are very well monitored by signaling pathways called checkpoints which constantly make sure that upstream events are successfully completed before the initiation of the next phase. It's in fact important that alterations in duplication of the DNA during S phase do not occur, to avoid the segregation of aberrant genetic material to the daughter cells hence ensuring accurate genetic information's transmission throughout cellular generations. Lack of fidelity in cell cycle processes creates a situation of genetic instability which contributes to the development of cancer desease. In cancer, the genetic control of cell division is altered resulting in a massive cell proliferation. Mutations mainly occur in two classes of genes: proto-oncogenes and tumor suppressor genes. In normal cells the proto oncogenes products act at different levels in pathways that stimulate proper cell proliferation while the mutated proto-oncogenes or oncogenes can promote tumor growth due to uncontrolled cell proliferation. Tumor-suppressor genes normally keep cell numbers down, either by halting the cell cycle and thereby preventing cellular division or by promoting programmed cell death. When these genes are rendered non-functional through mutation, the cell becomes malignant. Defective proto-oncogenes and tumor-suppressor genes act similarly at a physiologic level: they promote the inception of cancer by increasing tumor cell number through the stimulation of cell division or the inhibition of cell death or cell cycle arrest. Uncontrolled cell proliferation which evolves in cancer can occur through mutation of proteins important at different levels of the cell cycle such as CDK, cyclins, CKI and CDK substrates. Defects in cell cycle checkpoints can also result in gene mutations, chromosome damages and aneuploidy all of which can contribute to tumorigenesis.

Figure 1. Schematic summary of the levels of regulation of the cyclin dependent kinases (Cdk). 1 and 2. Synthesis and degradation of cyclins at specific stages of the cell cycle. 3. Association of cdks to cyclins in order to be active. 4. Activation of the cdk/cyclin complexes by CAK. 5. Inactivation of cdk/cyclin complexes by phosphorylation at thr14 and tyr15 (5a) and reactivation by phosphatases acting on these sites (5b). 6. Cdk inhibitor proteins (CKI) preventing either the assembly of cdk/cyclin complexes (6a) or the activation of the cdk in the complex (6b). The activated cdk/cyclin complexes can phosphorylate substrates necessary for transition to the next cell cycle phase.

Targeting cell cycle regulators in cancer

Cyclins and their associated cyclin-dependent kinases (CDKs) are the key drivers of the cell cycle and specific transitions in the cell cycle are controlled solely by specific CDKs. When this specificity is maintained in tumour cells, selective inhibition of these kinases presents a potential attractive strategy to tumour therapy, suggesting that a therapeutic window could be achieved. In normal cells, commitment for the progression through the cell cycle and beginning of replication process is controlled by cyclin D-CDK4/6 at the restriction point (Musgrove et al., 2011). CDK4 and CDK6 initiate the phosphorylation of the retinoblastoma (RB) protein family, resulting in dissociation and thereby activation of E2F transcription factors which initiate the S phase gene expression program, including the expression of both cyclin E and CDK2, resulting in further RB phosphorylation and ultimately S phase entry (Malumbres and Barbacid, 2009). Deregulation of the restriction point is a common event in cancer, yet CDK4/6 is a potential therapeutic target in only a subset of cancers. Many oncogenes overcome the restriction point by promoting CDK4/6 activity (Huillard et al., 2012). CDK4 can be activated more directly by point mutation/amplification or via amplification of CCND1 (cyclin D1) (Curtis et al., 2012 Kim and Diehl, 2009), or indirectly via mutation, silencing by methylation or homozygous deletion of CDKN2A (encoding p14ARF and p16INK4A) (Pinyol et al., 1997). Elevated levels of phosphorylated RB and relatively low levels of p16INK4A may provide biomarkers of CDK4/6 dependence (Konecny et al., 2011). Mouse double knockout studies of CDK4 and CDK6 suggest that the CDK4/6 kinases are only essential in specific tissue compartments (Malumbres et al., 2004), presenting a therapeutic window where tumour cells are more reliant on CDK4/6 than many proliferating normal tissues. CDK4/6 inhibition has great promise for the treatment of multiple cancer types, and multiple clinical studies are ongoing.

Cyclin B-CDK1 activity, as mentioned before, governs mitotic entry and is tightly controlled by an intricate network of feedback loops (Lindqvist et al., 2009). A number of potential issues make CDK1 a less attractive target than CDK4/6. CDK1 is essential for mitosis in most normal cells, which may limit the ability to dose CDK1 inhibitors in the clinic. If CDK1 inhibition causes a reversible G2 arrest in cancer cells, it is unclear whether a CDK1 inhibitor could be dosed sufficiently to achieve tumour control and studies are undergoing. Polo-like kinase 1 (PLK1) and Aurora kinase A (AURKA), promote progression through mitosis. Inhibition of these kinases presents a potential therapeutic opportunity through inhibiting appropriate progression through mitosis. PLK1 is a serine/threonine kinase involved in centrosome maturation, spindle formation, chromosome segregation and cytokinesis (Strebhardt, 2010). Besides its mitotic functions, PLK1 is essential for inactivating or removing key components of the DNA damage response, such as CHK1 (via Claspin), WEE1 and 53BP1, to inactivate checkpoint signalling and promote cell cycle resumption (Strebhardt, 2010). Inhibition of PLK1 causes cells to arrest in mitosis with a monopolar or disorganised spindle followed by mitotic cell death (Lens et al., 2010). The Aurora kinase family members (A, B and C) each coordinate distinct processes during cell division. AURKA is critical for centrosome maturation and proper formation of the mitotic spindle. Selective inhibition of AURKA leads to abnormal mitotic spindles and a temporary mitotic arrest followed by chromosome segregation errors as cells exit mitosis. The amplification and overexpression of AURKA has been reported in many human tumours, including breast, colon, neuroblastoma, pancreatic and ovarian cancers, with high AURKA expression levels being associated with poor prognosis and genomic instability (Lens et al., 2010). This makes AURKA an attractive anti-mitotic drug target and as in fact, AURKA inhibitors are currently being evaluated pre-clinically and in clinical trials. Clinical data with mitotic kinase inhibitors have not yet been really promising. The AURKA-selective inhibitor MLN8237 (alisertib) had low levels of activity in a phase II study in unselected ovarian cancer (Matulonis et al., 2012), and only modest activity was seen in initial clinical trials of PLK1 inhibitors (Olmos et al., 2011). However, none of these studies have yet selected for potentially sensitive tumours, so further insights in determining the most responsive tumors are required in future trials.

DNA damage checkpoint

A faithful transmission of genetic informations from one cell to its daughters requires the ability of a cell to survive to spontaneous and induced DNA damage to minimize the number of heritable mutations. To achieve this fidelity, cells have evolved surveillance mechanisms composed by an intricate network of checkpoint proteins that tells the cell to stop or delay the cell cycle progression providing enough time for DNA repair. When the damage could not be repaired cells undergo apoptosis. Many different lesions can occur in the cells which are coupled to different repair mechanisms. First, normal metabolic processes or exposure to external ionizing radiations generate free oxygen radicals and can break the phospho diester bonds in the backbone of the DNA helix (single strand break). When two of these breaks are close to each other but on opposite DNA strands, a double strand break (DSB) is present. Second, alkylating agents can modify purine bases and can cause intra strand or inter strand crosslinks. Inhibitors of DNA topoisomerase can cause DNA lesions leading to enhanced single or double strand break depending on which topisomerase is inhibited and on the phase of the cell cycle. Different mechanisms are required to repair the damage to the DNA backbone or to the DNA bases and the repairing mechanisms may also vary depending on the different phases of the cell cycle. The DNA damage checkpoint activation pathway is the response to a variety of internal factors (e.g. incomplete DNA replication due to stalled replication forks, reactive oxygen species-ROS) and external sources (e.g. UV light, ionizing radiation-IR, DNA-damaging chemotherapeutic agents). The checkpoint activation is part of the signaling network (the DNA damage response) that involves multiple pathways including checkpoints, DNA repair, transcriptional regulation and apoptosis (Bartek and Lukas, 2007 Branzei and Foiani, 2008). When DNA damage occurs, a signal transduction pathway cascade is activated in which sensor proteins recognize the damage and transmit signals that are amplified and propagated by adaptors/mediators to the downstream effectors that connect the checkpoint with the cell cycle machinery and final cell fate. Generally the cell cycle progression is hampered at the stage in the cell cycle where the cell was at the time of injury: before entry in S phase (G1/S phase checkpoint), during S phase progression (intra S phase or S phase checkpoint), before mitotic entry (G2/M phase checkpoint) or during mitosis (mitotic spindle checkpoint). The cell cycle arrest gives cell time to fix the damage by activating a series of DNA repair pathways. If the damage exceeds the capacity for repair, pathways leading to cell death are activated mostly by apoptosis (by p-53 dependent and independent pathways) (Zhou and Elledge, 2000).

Chk1 protein kinase is one of the main component of DNA damage checkpoints pathways and represent a vital link between the upstream sensors of the checkpoints (i.e. ATM and ATR) and the cell cycle engine (i.e. cdk/cyclins) (Zhou and Elledge, 2000 Stracker et al., 2009). A brief description of its network is herein summarized to show just an example of how in general checkpoints proteins are strictly interconnected and inter-related each others. Chk1 regulates the checkpoints by targeting the Cdc25 family of dual specificity phosphatases, Cdc25A at the G1/S and S phase checkpoints and Cdc25A and Cdc25C at the G2/M checkpoint.(Peng et al., 1997 Mailand et al., 2000) Phosphorylation of Cdc25A by Chk1 at multiple sites increases proteosomal degradation of the phosphatase and inability of Cdc25A to interact with its cyclin/cdks substrates. Chk1 phosphorylates Cdc25C at ser216, leading to formation af a complex with 14-3-3 proteins and cytoplasmic sequestration of the phosphatase (Peng et al., 1997 Mailand et al., 2000 Zhao et al., 2002), thus avoiding activation of the cyclinB1-CDK1 complex which regulates the entry in mitosis. Chk1 is activated after DNA damage, which ultimately causes single strand (ss) DNA breaks, by ATM- and ATR-dependent phosphorylation of C-terminal residues (ser317 and ser345). In particular, after formation of ssDNA breaks (induced for example by UV, replication stresses, DNA damaging agents), replication protein A (RPA) binds to ssDNA and recruits Rad17/9-1-1 and ATR/ATRIP complexes, leading to Chk1 phosphorylation. Chk1 activation by ATR also requires mediators such as claspin, BRCA1, TOBP1. Indirectly, as ssDNA breaks also serve as an intermediate of double strand DNA (dsDNA) breaks, ATM too is involved in Chk1 activation. ATM is recruited at the level of DSBs (induced by IR for example) by the MRN complex leading to Chk2 activation. ATM and MRN mediate DSB resection leading to ssDNA formation as an intermediate structure of DNA repair, leading to Chk1 activation through RPA/ATR-ATRIP recruitment (Bartek and Lukas, 2007 Gottifredi and Prives, 2005 Jazayeri et al., 2006).

Chk1 also plays a role in the mitotic spindle checkpoint which ensures the fidelity of mitotic segregation during mitosis, preventing chromosomal instability and aneuploidy (Carrassa et al., 2009 Zachos et al., 2007 Suijkerbuijk and Kops, 2008 Chilà et al., 2013).

Targeting cell cycle checkpoints as therapeutic strategy in cancer

The DNA damage response requires the integration of cell cycle control via checkpoint signalling to allow time for repair to prevent DNA damage before DNA replication and mitosis take place. The importance of checkpoints pathways in the cellular response to DNA damage (both endogenous and exogenous) is at the basis of the use of checkpoint inhibitors to increase the efficacy of cancer radio- and chemo-therapy. Chemo- and radio-therapy are strong inducers of the DNA damage response pathways being able to cause different types of DNA damage and variably able to activate checkpoints, and the abrogation of these checkpoints can potentiate the cytotoxic activity of various anticancer agents (Poehlmann and Roessner, 2010). Targeting the S and G2 checkpoints has been considering attractive for cancer therapy because loss of G1 checkpoint control is a common feature of cancer cells (due to mutation of tumor suppressor protein p53), making them more reliant on the S and G2 checkpoints to prevent DNA damage triggering cell death, while normal cells also depend on a functional G1 checkpoint (Dai and Grant, 2010 Ma et al., 2011). Experimental evidence showed that inhibiting the S and G2 checkpoints by inactivation of ATR or CHK1 abrogated DNA damage-induced G2 checkpoint arrest and sensitized cancer cells to a variety of DNA-damaging chemotherapeutic agents (Carrassa et al., 2004 Ganzinelli et al., 2008 Massagué, 2004). Furthermore, oncogenic replicative stress may render cancer cells sensitive to inhibitors that prevent the S and G2 checkpoints as single agents. As mentioned previously, CHK1 is a key signalling kinase involved in the intra-S phase and G2/M checkpoints (Kastan and Bartek, 2004). In response to replication stress or genotoxic insults, CHK1 is activated via ATR-dependent phosphorylation. During unperturbed S phase, CHK1 controls replication fork speed and suppresses excess origin firing (Petermann et al., 2010), prevents premature activation of cyclin B-CDK1 and may be involved in spindle checkpoint signalling (Zachos et al., 2007 Chilà et al., 2013, Carrassa and Damia, 2011). Oncogene driven replication is abnormal and results in high levels of replication stress, and inhibition of CHK1 may increase the replication stress to sufficiently high levels to be lethal as a single agent in certain contexts (Jazayeri et al., 2006 Syljuåsen et al., 2005). The tyrosine kinase Wee1, together with Chk1, has also to be considered a crucial checkpoint protein controlling S and G2 checkpoint (Figure 2). The WEE1 kinase prevents mitotic entry via inhibitory phosphorylation of CDK1 at Tyr15 (Lindqvist et al., 2009). Recently, it is becoming clear that WEE1 is also required for the maintenance of genome integrity during DNA replication (Sørensen and Syljuåsen, 2012 Beck et al., 2012). WEE1 controls CDK1 and CDK2 activity during S phase, thereby suppressing excessive firing of replication origins, promoting homologous recombination, and preventing excessive resection of stalled replication forks (Beck et al., 2012 Krajewska et al., 2013).

Figure 2. Schematic representation of the role of Chk1 and Wee1 in regulation of the CDK-cyclin complexes involved in S phase and M phase entry.

Thus both Chk1 and Wee1 are required during normal S phase to avoid deleterious DNA breakage, and thereby prevent loss of genome integrity in the absence of exogenous DNA damage (Sørensen and Syljuåsen, 2012). Several Chk1 and Wee1 inhibitors have now been developed and tested in combination with DNA damaging agents to increase their efficacy, especially in tumors with a defective G1/S checkpoint (e.g. p53 defects) (Carrassa and Damia, 2011 Stathis and Oza, 2010). WEE1 inhibitors have been developed, and some have entered into clinical trials but clinical data are still limited. The pyeazolo-pyrimidine derivative MK-1775 is the most potent and highly selective inhibitor of Wee1, and has recently reached phase I (in combination with gemcitabine, cisplatin, or carboplatin) and II studies (in combination with paclitaxel and carboplatin in ovarian cancer) (Stathis and Oza, 2010 De Witt Hamer et al., 2011). Most research has focused on the development of CHK1 inhibitors, which have entered clinical studies. UCN 01 was the first of this type of inhibitor to enter clinical trials, but after Phase II trials it was discontinued owing to dose-limiting toxicities and a lack of convincing efficacy that was probably due to poor specificity and pharmacokinetics. The newer, more specific inhibitors of CHK1 have generally been combined with gemcitabine in Phase I studies, in which myelosuppression was the major toxicity that led to the termination of the trials, and no efficacy data have yet been presented (Carrassa and Damia, 2011 Blasina et al., 2008). Recently, a selective orally available inhibitor developed from a high-throughput screening hit, GNE-900, gave promising pre-clinical studies and is now undergoing Phase I clinical trials (Blackwood et al., 2013).

Synthetic lethality approach in cancer therapy

The most promising prospect for the future of cancer treatment seems to be the exploitation of dysregulated DNA Damage Response, by the synthetic lethality approach. The synthetic lethality concept states that mutations of two different genes are not lethal in the cells when they occur at once, but are synthetically lethal, causing cells to die, if they occur simultaneously. Synthetic lethal interactions have been widely reported for loss and gain of function mutations. The synthetic lethality-driven approach offers the ideal cancer therapy as it allows indirect targeting of non-druggable cancer-promoting lesions with pharmacological inhibition of the druggable synthetic lethal interactor and as it should be exclusively selective for cancer cells, and well tolerated by healthy normal cells, that lack the cancer-specific mutation, with a wide therapeutic window (Kaelin Jr, 2005 Canaani, 2009). This concept is at the basis of the efficacy in preclinical systems of PARP inhibitors in homologous recombination defective cells, due to mutation of genes such as BRCA1/BRCA2 and it has already undergone proof-of-principle in the clinical setting. Substantial durable antitumor activity was observed after treatment with PARP inhibitors in patients with BRCA1/2-mutated cancers, including ovarian, breast and prostate cancers (Bryant et al., 2005 Fong et al., 2009). Chk1 inhibition has been proposed as a strategy for targeting FA (Fanconi Anemia) pathway deficient tumors. In fact, tumor cells deficient in the FA pathway are hypersensitive to Chk1 inhibition, suggesting a possible use of these inhibitors in FA deficient tumors (Chen et al., 2009). The FA pathway is a DNA repair pathway required for the cellular response to different DNA damaging agents, including cross-linking agents (e.g. cis-platinum) in cooperation with the homologous recombination pathway. A range of sporadic tumors with genetic and epigenetic disruption of the FA genes have been reported. Hyperactive growth factor signalling and oncogene-induced replicative stress increase DNA breakage that activates the ATR-CHK1 pathway, and some examples of the synthetic lethality of checkpoint or DNA repair inhibitors in cells harbouring activated oncogenes have been identified. ATR knockdown was synthetically lethal in cells transformed with mutant KRAS (Gilad et al., 2010), and inhibition of CHK1 and CHK2 significantly delayed disease progression of transplanted MYC-overexpressing lymphoma cells in vivo (Ferrao et al., 2011).

Many recent studies with a high throughput siRNA screening approach led to identification of other possible target genes synthetically lethal with Chk1 inhibitors. Recently two distinct siRNA high-throughput screening identified Wee1 as in synthetic lethality with Chk1 (Davies et al., 2011 Carrassa et al., 2012) and combined treatment of Chk1 and Wee1 inhibitors showed a strong synergistic cytotoxic effect in various human cancer cell lines (ovary, breast, prostate, colon). The strong in vitro synergistic effect of the combination translates to tumor growth inhibition in vivo (Carrassa et al., 2012 Russell et al., 2013). Simultaneous inhibition of CHK1 and WEE1 induces cell death through a general mis-coordination of the cell cycle (figure 3), which leads to DNA damage and collapsed replication forks during S phase (Carrassa et al., 2012 Guertin et al., 2012), and to premature mitosis directly from S phase. These data have been recently corroborated by other groups, suggesting that at least in solid tumors this drug combination could be a very new promising anticancer strategy deserving clinical investigation (Russell et al., 2013 Guertin et al., 2012). Many other successful synthetic lethality combinations exist and many more probably need to be explored and they will provide in the near future new potential effective tools for cancer therapy (Reinhardt et al., 2013 Curtin, 2012).

Figure 3. Schematic representation of the effects of Chk1 and Wee1 inhibition on CDK-CYCLIN complex regulation, that gets more activated being unphosphorylated.


Rare Disease Database

NORD gratefully acknowledges Stephanie Lin, NORD Editorial Intern from the University of Connecticut, Debby Tamura MS, RN, APNG and Kenneth H. Kraemer, MD, Dermatology Branch, Center for Cancer Research, National Cancer Institute, for assistance in the preparation of this report.

Synonyms of Xeroderma Pigmentosum

General Discussion

Xeroderma pigmentosum (XP) is a rare inherited skin disorder characterized by a heightened sensitivity to the DNA damaging effects of ultraviolet radiation (UV). The main source of UV is the sun. The symptoms of XP can be seen in any sun-exposed area of the body. The effects are greatest on the skin, the eyelids and the surface of the eyes but the tip of the tongue may also be damaged. In addition, approximately 25% of XP patients also develop abnormalities of the nervous system manifesting as progressive neuro-degeneration with hearing loss. People with XP have a 10,000-fold increased risk for developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. They also have a 2000-fold increased risk for cancer of the eye and surrounding ocular tissues. These symptoms appear early in life, typically before age 10 years.

XP is managed by preventative techniques (i.e., avoiding the sun, using sunscreen, wearing protective clothing) and regular screening for changes in the skin, vision, and neurologic status. Many symptoms can be treated with medication and/or surgery, but some cancers and neurologic problems can be life threatening.

XP is an autosomal recessive genetic condition caused by alterations (mutations) in nine different genes. Eight of the genes make up the nucleotide excision repair pathway (NER) that identities and repairs UV induced DNA damage. The ninth gene acts to bypass unrepaired damage.

Introduction

XP was first described in Vienna, Austria in 1870. In a dermatology textbook, Moriz Kaposi described a new disorder called xeroderma, which translates to “parchment skin.”

Signs & Symptoms

Individuals with XP are particularly sensitive to the DNA damaging effects of UV. Sources of UV include the sun, unshielded florescent light bulbs, mercury vapor lights and halogen light bulbs. Symptoms may differ from person to person, but typically impact the skin, eyes, and nervous system.

Cutaneous (Skin) Effects
Approximately half of XP patients develop blistering burns on sun exposed skin after minimal sun exposure (sometimes less than 10 minutes in the sun). These burns evolve over several days and may take greater than a week to heal. Sometimes these burns are so severe, child abuse is suspected. The other 50% of XP patients do not burn, but tan after sun exposure. However, both types of sun reactions result in the early onset of lentigos (freckling) of the skin.

Lentigos, are a patchy freckling of the skin, that appear before the age of two years in XP patients. The lentigos can be seen on all sun exposed skin, but are often seen first on the face. Lentigos are a sign of unrepaired UV damage in the skin. Repeated sun exposure also results in xerosis (dry, parchment-like skin) and poikiloderma a mixture of both hyper (increased) and hypo (decreased) skin pigmentation, skin atrophy (thinning of skin tissue), and telangiectasia (a widening of the small blood vessels, which produces red lines and patterns on the skin). In people who do not have XP, poikiloderma is typically seen in older adults, such as farmers or sailors, with many years of sun exposure.

For people with XP continuous repeated sun exposure has severe effects, resulting in the early development of precancerous skin spots (a.k.a., actinic keratosis) and skin cancers (see below).

Ocular (Eye) Effects
The eyelids and the surface of the eyes exposed to sunlight will usually be affected within the first decade of life.

Photophobia (light sensitivity, or pain upon seeing light) is common and is often noted in infancy or early childhood. The conjunctiva (the white portion of the eye) may show sunlight induced inflammation. People with XP also develop dry eye. Symptoms of dry eye include a feeling of ‘something being in the eye’, constant irritation and redness of the eye. Dry eye can also result in chronic inflammation and keratitis. Keratitis, or inflammation of the cornea (the clear outer dome of the eye) may also occur in response to sunlight. In severe cases, keratitis can result in corneal opacification (lack of transparency) and vascularization (an increase in blood vessel density). These combined effects may obscure vision, contributing to blindness. With repeated sun exposure, the lids of the eyes may atrophy (degenerate), eyelashes may fall out, leaving the eyes unprotected and contributing to vision loss.

Cancers of the eyelids, tissues surrounding the eyes, cornea and sclera (white part of the eye) can occur very early in life. Surgeries to remove ocular cancers can lead to lid abnormalities resulting in difficulty completely closing the eyes and vision loss. When cancers in or near the eye are large or invasive, the eye itself may need to be removed.

Neurologic (Nerve) Effects
Approximately 25% of patients with XP develop a progressive neurodegeneration. The degeneration can vary in time of onset and rate of progression. Symptoms of the neurodegeneration include: acquired microcephaly (a condition marked by smaller head size and structural changes in the brain), diminishing (or absent) deep tendon reflexes, progressive high-frequency sensorineural hearing loss (deafness caused by damage to the nerves of the inner ear), progressive cognitive impairment, spasticity (tightness/rigidity of the skeletal muscles), ataxia (poor muscle control and coordination), seizures, difficulty swallowing and/or vocal cord paralysis.

These issues are thought to arise due to the loss of nerve cells in the brain. The brains of XP patients with neurologic degeneration show atrophy (shrinkage) with marked dilation of the ventricles (fluid filled spaces in the middle of the brain). It is thought that accumulating unrepaired DNA damage in the brain cells results in their death, however, the source of this damage is has not been identified.

Neoplasias (Cancer)
Individuals with XP have a much greater chance of developing certain cancers. The risk of acquiring non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma) is 10,000 times greater than in the general population in patients under 20 years of age. Median age of first non-melanoma cancer for XP patients is 9 years old, which is 50 years earlier than in the general population. For melanoma skin cancer, the risk is 2,000 times greater for those with XP. The median age of onset is 22 years, which is 30 years earlier than in the general population.

Oral cavity neoplasms, specifically squamous cell carcinoma of the tip of the tongue (a non-pigmented sun exposed area), is common especially in dark skinned patients. Internal cancers that have been reported in individuals with XP include: glioblastoma of the brain, astrocytoma of the spinal cord, and cancer of the lung in patients who smoke, and rarely, leukemia (cancer of the white blood cells). Cancers of the thyroid, uterus, breast, pancreas, stomach, kidney, and testicles, have also been reported.

Causes

Inheritance
XP is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of a non-working gene for the same trait, one from each parent. If an individual inherits one normal gene and one non-working gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk for inheriting the disease is the same for males and females.

Parents who are blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, increasing the risk to have children with a recessive genetic disorder.

Relevant Genes
Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes arranged in 23 pairs. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genes are small parts of a chromosome. There are 9 different genes that may be altered in patients with XP and include: the DDB2 (XP-E) gene, located on the short arm of chromosome 11 (11p11.2), the ERCC1 gene, located on the long arm of chromosome 19 (19q13.32), the ERCC2 (XP-D) gene, located on the long arm of chromosome 19 (19q13.32), the ERCC3 gene (XP-G), located on the long arm of chromosome 2 (2q14.3), the ERCC4 gene (XP-F), located on the short arm of chromosome 16 (16p13.12), the ERCC5 (XP-B) gene, located on the long arm of chromosome 13 (13q33.1), the POLH gene (XP-V or variant), located on the short arm of chromosome 6 (6p21.1), the XPA gene, located on the long arm of chromosome 9 (9q22.33), and the XPC gene, located on the short arm of chromosome 3 (3p25.1). The proteins resulting from normal expression of these genes are involved in DNA repair and serve to recognize damaged DNA, remove the damage and fill in the resulting gap.

Affected Populations

XP affects males and females in equal numbers. Some gene mutations associated with XP are more common in certain parts of the world in these locations there is a higher prevalence of XP. In the United States and Europe, prevalence of XP is 1 in 1,000,000. In Japan, XP is much more common, affecting 1 in 22,000. Areas of North Africa (e.g., Tunisia, Algeria, Morocco, Libya, Egypt) and the Middle East (e.g., Turkey, Israel, Syria) also show an increased prevalence of XP.

Related Disorders

There are several genetically related disorders caused by mutations in genes in the nucleotide excision (NER) pathway. People with these diseases demonstrate very different symptoms despite having mutations in some of the same genes as XP patients. These conditions include Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, trichothiodystrophy (TTD), and UV-sensitive syndrome.

Cockayne syndrome is a rare form of dwarfism characterized by short stature, UV sensitivity, and prematurely aged appearance (progeria). Although prenatal growth is normal, developmental abnormalities usually appear within two years of life height, weight, and head circumferences tend to fall below the 5th percentile, and death usually occurs within the first two decades. For more information on this disorder, choose “Cockayne syndrome” as your search term in the Rare Disease Database.

Cerebro-oculo-facio-skeletal syndrome (COFS) is a genetic neuro-degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth, little or no neurological development, structural abnormalities of the eye, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs, and other parts of the body may also occur. COFS syndrome is inherited as an autosomal recessive genetic trait and is now considered to be part of the spectrum of disorders within Cockayne syndrome. For more information on this disorder, choose “cerebro oculo facio skeletal syndrome” as your search term in the Rare Disease Database.

Trichothiodystrophy (TTD) is a hereditary disorder characterized by short brittle hair that demonstrates alternating dark and light ‘tiger tail’ banding when examined through a polarized microscope. Symptoms may include photosensitivity, intellectual impairment, short stature, and microcephaly. Unlike, XP patients, TTD patients do not have an increased cancer risk. Individuals with TTD have a 20x increased risk of death before the age of 10 (typically due to infections). Patients with TTD tend to have complications during their gestations and exhibit neonatal abnormalities. For more information on this disorder, choose “trichothiodystrophy” as your search term in the Rare Disease Database.

UV-sensitive syndrome is a form of photosensitivity that does not involve pigmentary abnormalities or nervous system deficits. People with UV sensitive syndrome develop sun burns after very minimal sun exposure but do not have increased cancer risk.

In addition, there are patients who demonstrate combinations of XP with other NER disorders, most notably, xeroderma pigmentosum with Cockayne syndrome (XP/CS) and xeroderma pigmentosum with trichothiodystrophy (XP/TTD). There have been a few patients reported with cerebraloculofacioskeletal syndrome and trichothiodystrophy (COFS/TTD) and Cockayne syndrome and trichothiodystrophy (CS/TTD). Individuals with these ‘overlap’ syndromes show a mixture of the symptoms that are normally present in both of the disorders. For example, those with XP/CS show facial freckling (typical of XP), as well as short stature, sunken eyes and wasting (typical of CS). XP/CS differs from XP alone in that there is dysmyelination (defective structure/function of the myelin sheath) along with the neuronal degeneration typically seen in people with XP and neurologic disease.

Diagnosis

XP is typically first diagnosed on the basis of clinical symptoms (see “Signs & Symptoms”), many patients with XP do not have a past family history of the condition., (see “Causes”).

Molecular genetic testing for mutations in the XP genes is available to confirm the diagnosis.

Standard Therapies

Prevention
Rigorous sun (UV) protection is necessary beginning as soon as the diagnosis is suspected to prevent continued DNA damage and disease progression. Individuals with XP should avoid exposing the skin and eyes to ultraviolet (UV) radiation. This can be done by wearing protective clothing such as hats, hoods with UV blocking face shields, long sleeves, pants, and gloves. High sun-protective factor (SPF) sunscreens, UV-blocking glasses with side-shields, and long hair can also provide protection.

The XP patient’s surroundings (e.g., home, school, and work) should be tested for levels of UV using a UV light meter. The meter can help identify areas of increased UV and sources of damaging UV (e.g., from halogen, and unshielded florescent light bulbs and mercury vapor lamps) can be eliminated from the environment. Since UV can pass through glass, widows in homes, schools, work places and cars of XP patient should be treated with UV blocking film.

Vitamin D is an essential vitamin, which helps maintain healthy bones. Vitamin D is manufactured by the interaction of UV with the skin. Since people with XP avoid UV, oral dietary supplements may be taken as needed to avoid complications of inadequate vitamin D levels.

Certain carcinogens in cigarette smoke damage DNA in ways similar to UV and exposure to second hand cigarette smoke should be avoided. XP patients who have smoked cigarettes have developed lung cancers.

Dermatologic Care
The skin (including the scalp, lips, tongue, and eyelids) should be examined by a dermatologist every 6-12 months (or more often if necessary) to detect precancerous and cancerous lesions. Prompt removal of any skin cancers is necessary to prevent further growth or spread of the lesions. Affected individuals and guardians of children should be instructed in skin examination techniques to aid in the early detection of possible skin cancers.

Individuals should also undergo routine eye exams by an ophthalmologist. The eyelids should be examined for ectropion (drooping and sagging), entropion (inward rotation, which may cause eye irritation), and pterygia/pinguecula (benign growths on the surface of the eyes). The cornea, which covers the eye, should be assessed for clouding, and the eyes should be tested for dryness in the Schirmer test, a filter paper is placed under the eyelids to measure absorption of tears. A dilated eye exam is important to assess for any changes in the retina (back of the eye).

Basic neurologic examinations including measuring the occipital frontal circumference (to determine the presence of microcephaly) and assessing for the presence of deep tendon reflexes, should be part of the routine care of an XP patient. Hearing exams should be done on a regular basis to assess for early onset hearing loss, which is an indicator of XP with neurologic disease. If hearing loss is detected, hearing aids can be very beneficial in correcting the deficits. If neurologic problems are identified, more in depth exams by a neurologist are indicated. In addition, MRIs can assess for changes that are commonly seen in the brains of XP patients who have neurodegeneration. XP patients who develop neurologic disease can have a peripheral neuropathy, which may be assessed by testing nerve conduction velocity (speed of electrical transmission) through the nerves of the arms and legs.

Treatment of Skin Cancers
Small, premalignant skin lesions, (e.g., actinic keratosis) can be treated by freezing with liquid nitrogen. For larger areas of damaged skin, topical creams such as 5-fluorouracil or imiquimod may be applied dermatome shaving and dermabrasion have been used for larger areas of skin. Small skin cancers on the trunk and extremities can be treated with electrodessication and curettage, or surgical excision. Deeply invasive skin cancers or skin cancers on the face and areas that require tissue-sparing techniques can be treated with Mohs micrographic surgery. In severe cases, large portions of skin may be re-grafted (or replaced) with sun-protected skin. X-ray therapy can be used to treat inoperable or larger neoplasms or as adjuvant therapy to surgery. The oral retinoids isotretinoin or acitretin can be used to prevent new skin neoplasms, but have many side effects including: liver toxicity, elevated levels of cholesterol, calcification of the ligaments and tendons, and premature closure of the growing bone shafts. These retinoid drugs are known to cause birth defects and are contraindicated in pregnant women or women who are trying to become pregnant.

Treatment of XP Eye Abnormalities
Lubricating eye drops used frequently keep the cornea moist and protects against the inflammatory effects of dry eye. Soft contact lenses can be worn to protect against mechanical trauma caused by deformed eyelids. It is best to start with simpler treatments first.

Neoplasms of eyelids, conjunctiva, and cornea can be treated with surgery. In some cases, corneal transplantation has been attempted to correct UV induced ocular damage and corneal clouding. However, the transplants may not be successful due to immune rejection. Unfortunately, immunosuppressive drugs used to prevent immune rejection may lead to additional skin cancers.

Treatment of XP Neurologic Abnormalities
Neurologic abnormalities are associated with increased high frequency sensory-neural hearing loss. The hearing loss is progressive (gets worse over time) and can be treated with hearing aids. Cognitive delays can be seen in childhood and special education classes, physical and occupational therapies along with UV safe accommodations at school are very helpful for XP children. As they get older, people with XP neurologic disease also experience increasing ataxia, dysphagia (difficulty swallowing) and dysarthria (difficulty speaking) as the condition progresses. They may require wheel chairs, feeding tubes and long term nursing care.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
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    References

    TEXTBOOKS
    Tamura D, DiGiovanna J J, and Kraemer K H. Xeroderma pigmentosum. In: Treatment of Skin Disease – Comprehensive Therapeutic Strategies, Third Edition Mark G. Lebwohl, Warren R. Heymann, John Berth-Jones and Ian Coulson (eds). London, Saunders, Elsevier. 2010: 789-792.

    JOURNAL ARTICLES
    Tamura D, DiGiovanna JJ, Khan SG, Kraemer KH. Living with xeroderma pigmentosum: Comprehensive photoprotection for highly photosensitive patients. Photodermatology, Photoimmunology and Photomedicine 201430 (2-3):146-152.

    Brooks BP, Thompson AH, Bishop RJ, Clayton JA, Chan CC, Tsilou ET, Zein WM, Tamura D, Khan SG, Ueda T, Boyle J, Oh K S, Imoto K, Inui H, Moriwaki S, Emmert S, Iliff N T, Bradford P, Digiovanna J J, and. Kraemer K.H. Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology 2013120 (7):1324-1336.

    Lai J-P, Liu T-C, Alimchandani M, Liu Q,, Aung PP, Matsuda K, Lee C-C R, Tsokos M, Hewitt S, Rushing EJ, Tamura D, Levens DL, DiGiovanna JJ, Fine HA, Patronas N, Khan SG, Kleiner DE, Oberholtzer JC, Quezado MM and Kraemer KH. The influence of DNA repair on neurologic degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D) Acta Neuropathologica Communications 2013: 1:4 DOI: 10.1186/2051-5960-1-4.

    Totonchy MB, Tamura D, Pantell M S, Zalewski C, Bradford, PT, Merchant SN, Nadol J, Khan S G., Schiffmann R, Pierson TM, Wiggs E, Griffith AJ., DiGiovanna J J, Kraemer K H and Brewer CC. Auditory analysis of xeroderma pigmentosum, 1971-2012: Hearing function, sun sensitivity and DNA repair predict neurologic degeneration. Brain 2013136 (Pt 1):194-208.

    Digiovanna JJ and Kraemer KH. Shining light on xeroderma pigmentosum. J Invest Dermatol. 2012 Mar132(3 Pt 2):785-96. doi: 10.1038/jid.2011.426. Epub 2012 Jan 5.

    Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle J, Oh K-S, Imoto K, Inui H, Moriwaki S-I, Emmert S, Pike K M, Raziuddin A, Plona TM, DiGiovanna J J, Tucker MA, and Kraemer KH. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterizes the role of DNA repair. J. Medical Genetics 201148:168-176.

    Christen-Zaech S, Imoto K, Khan SG, Oh K-S, Tamura D, DiGiovanna JJ, Boyle J, Patronas NJ, Schiffmann R, Kraemer KH and Paller AS.Unexpected occurrence of xeroderma pigmentosum in an uncle and nephew. Arch Dermatol. 2009 Nov 145(11): 1285–1291.

    Kraemer KH, Patronas NJ, Schiffmann R, Brooks B P, Tamura D, and DiGiovanna JJ. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 2007145:1388–1396.

    Berneburg M, Krutmann J. Xeroderma pigmentosum and related syndromes. Hautarzt. 200354:33-40.

    Zghal M, et al. A whole family affected by xeroderma pigmentosum: clinical and genetic particularities. Ann Dermatol Venereol. 2003130:31-36.

    Wesiberg NK, Varghese M. Therapeutic response of a brother and sister with xeroderma pigmentosum to imiquimod 5% cream. Dermatol Surg. 200228:513-23.

    Nelson BR, et al. The role of dermabrasion and chemical peels in the treatment of patients with xeroderma pigmentosum. J Am Acad Dermatol. 199532:623-26.

    Kondoh M, et al. Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age. J Am Acad Dermatol.199431:993-96.

    INTERNET
    Kraemer KH, DiGiovanna JJ. Xeroderma Pigmentosum. 2003 Jun 20 [Updated 2016 Sep 29]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1397 Accessed February 6, 2017.

    Years Published

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    Conclusions

    The Smc family of proteins has critical roles in the DNA damage response of organisms from yeast to man. The Smc1/3 cohesin complex promotes DNA double-strand break (DSB) repair through homologous recombination (HR) between sister chromatids, presumably by holding sister chromatids in proximity to help strand invasion. Cohesin is also required for DNA damage checkpoint activation. The condensin complexes are required for DNA damage checkpoint activation, DNA repair, and rDNA stability. The Smc5/6 complex facilitates DSB repair through HR between sister chromatids and does so in the same pathway as cohesin. The Smc5/6 complex has additional roles in DNA repair, including resolution of collapsed replication forks and rDNA maintenance.

    Many outstanding questions still remain in this area. First, the detailed molecular mechanisms by which the Smc proteins mediate DNA repair are not understood. In particular, in the cases of cohesin and condensin, it is unclear whether their DNA repair functions are separable from their major functions in sister-chromatid cohesion and chromosome condensation. Second, more needs to be learned about how the DNA repair functions of the Smc complexes are regulated during the cell cycle. Finally, the coordination and crosstalk among the three Smc complexes in the DNA damage response need to be further examined. Both cohesin and the Smc5/6 complex act in the same pathway to repair DSBs through HR between sister chromatids. How do they communicate with each other? Likewise, both condensin and the Smc5/6 complex are required for rDNA stability in yeast. Is this function of condensin and Smc5/6 conserved in higher eukaryotes? Do these two complexes function in the same or different pathways? Future studies aimed at addressing these questions will greatly advance our understanding of the molecular mechanisms underlying chromosome maintenance and genome stability.

    Mutations of the Smc complexes and their regulators have been linked to human diseases, including cancer. A better understanding of how these complexes protect genomic stability will help us understand the molecular basis of disease phenotypes and may ultimately lead to strategies that exploit the dysregulation of the Smc proteins to treat these human diseases.


    The Institute for Creation Research

    In the mid-1800s, a mild Augustinian friar named Gregor Mendel crossbred pea plants and pioneered the beginnings of understanding inherited traits. Genetics has come a long way since then.

    Neither Mendel nor Charles Darwin knew anything about the incredible molecule of life, DNA. Today, papers are published daily in science journals describing new discoveries of DNA&rsquos role as a regulator and repairman.

    Scientists have known for decades that DNA can be damaged by too much sun (UV radiation) or exposure to harmful chemicals and carcinogens. Upon examination of damaged DNA, the researchers discovered that whole families of submicroscopic repair enzymes (tiny machines) were constantly restoring the damaged DNA. 1 It has been estimated that as many as one million individual molecular lesions (trauma) of DNA occur per cell per day that need repair. 2 Since we are designed with trillions of cells, you can imagine the sheer number of tiny repair enzymes hard at work in each person!

    Now a U.S.C. Dornsife study reveals a molecule that &ldquowalks&rdquo damaged DNA to a kind of emergency room in the cell. 3 Using florescent markers, scientists &ldquosaw how the cell launches an emergency response to repair broken DNA strands from a type of tightly-packed DNA, heterochromatin.&rdquo Heterochromatin are areas of the genome in which little is known due to their lack of protein-coding genes. However, researchers think that damage in some heterochromatin may possibly lead to cancer.

    The study describes that after the strands of DNA are injured, tiny filaments of a protein called actin form, producing a road to the edge of the nucleus. This is what the myosin (the &ldquoparamedics&rdquo) use to travel along the actin road with the broken DNA. The &ldquoemergency room&rdquo is a complex pore at the nuclear edge. As Assistant Professor Irene Chiolo said, &ldquoWhat we think is happening here is that the damage triggers a defense mechanism that quickly builds the road, the actin filament, while also turning on an ambulance, the myosin.&rdquo 3

    In an interesting admission, the article stated that repetitious DNA sequences in heterochromatin were for several decades referred to as &ldquojunk DNA.&rdquo But with more research &ldquostudies have shown that repeated DNA sequences are in fact essential for many nuclear activities.&rdquo 3

    Creationists believe God doesn&rsquot make junk. In addition, these numerous submicroscopic protein machines walking along countless actin highways reflect what the apostle Paul said in Romans 1:20&mdashGod&rsquos creation is &ldquoclearly seen.&rdquo

    1. Sherwin, F. 2004. Mending Mistakes&mdashThe Amazing Ability of Repair. Acts & Facts. 33 (6) and Thomas, B. 2008. DNA Repair Enzymes: Vital Links in the Chain of Life. Creation Science Update. Posted on ICR.org August 27, 2008, accessed July 1, 2018.
    2. Lodish, H. et al. 2013. Molecular Biology of the Cell, 5th ed. New York: Freeman, 151.
    3. &ldquoWalking molecules&rdquo haul away damaged DNA to the cell&rsquos emergency room. PhysOrg. Posted on phys.org June 20, 2018, accessed June 21, 2018.

    * Mr. Frank Sherwin is Research Associate, Senior Lecturer, and Science Writer at the Institute for Creation Research.


    The Dangers of Being an Astronaut

    Ever since I was a young girl, the night sky amazed me. Looking up at the stars and the moon, I used to wish I could see them up close, which is why when I first learned about astronauts, I was awestruck. Being an astronaut is perhaps one of the most challenging jobs in the world and comes along with many risks. While space travel is a relatively new concept that we do not know much about, we have been able to study its effects on human beings, with the conclusion being that there are some damaging results to the astronauts’ DNA. This damage is mainly caused by the astronauts’ exposure to space radiation.

    The International Space Station (ISS) is where the astronauts stay when in space and the ionizing radiation (IR) sources, where the ISS orbits, include three primary radiation sources. Galactic cosmic rays (GCRs) range from protons to Fe-ions, solar particle events (SPEs), and electrons and protons trapped in the Van Allen Belts (TPs) outside the spacecraft. This creates a complex radiation environment around the ISS, and inside of it as well (Furukawa et al., 2020). Primary GCRs produce many secondary particles through projectile and target fragmentation in the ISS shielding materials and the bodies of astronauts. The flux of primary TPs increases as the altitude of the ISS increases and so they play a role in either increasing or decreasing the exposure of astronauts to radiation in Low-Earth Orbits (LEO)(Benton and Benton, 2001).

    Solar ultraviolet (UV) radiation is part of the natural energy that is produced by the sun and reaches the Earths’ surface. UV has different effects on biological processes and so it is classified as UV-C, UV-B, and UV-A. UV-C does not reach the surface of the earth, as UV-B and UV-A do, as it is eliminated by the stratospheric ozone layer (Singh et al., 2017). Although sunlight is beneficial for life on earth, it does still contain a harmful amount of UV-B radiation which causes damage to important cellular components, such as DNA, RNA, protein, and lipids (Britt, 1996). DNA, which stores genetic information, has its structure directly altered by UV radiation. Cyclobutane pyrimidine dimers (CPDs) are the main UV-induced photoproducts and account for approximately 75% of DNA damage (Sancar, 2004). The environment of space consists of much short-wavelength solar UV radiation, among a variety of different types of radiation and so astronauts are exposed to a very large amount of space radiation. In fact, UV-C is much more prevalent in space, and at a higher intensity which is quite dangerous for human beings.

    Radiation-induced DNA damage includes base damage, single-strand breaks (SSBs), and double-strand breaks (DSBs). DSBs are the most severe and if not repaired correctly, cell death, cellular senescence, and tumorigenesis may occur (Sankaranarayanan et al., 2013). It is important to consider the energy of radiation when exposed to it in space versus on earth. When one is exposed to radiation on the ground, the radiation levels are at low-LET (linear energy transfer) and include X-rays and y-rays. GCR on the other hand contains high-LET radiation such as energetic protons and heavy particle beams, i.e., HZE particles. (Ohnishi and Ohnishi, 2004) High-LET radiation exposure induces complex DNA damage as it leads to dense ionization along the radiation tracks of such particles. These regions of damage are referred to as complex/clustered DNA damage (lesion) and when compared to normal DNA damage, they are much more difficult to repair (Rydberg 2001), So, even if one were to be exposed to the same amount of radiation in space as on the ground, the quality and amount of DNA damage that occurs will be different. Clustered DNA damage induced by high-LET radiation exposure is detected using the comet assay or agarose gel electrophoresis.

    Chromosomal Aberrations (CAs) are used as cytogenetic biomarkers for exposure to IR and other DNA-damaging agents, and the frequency of CAs in peripheral lymphocytes may be associated with the risk of cancer. CAs have been analyzed in spacecraft crews since the 1960s and the frequency of total CAs is higher at postflight than at preflight- usually when the flights are longer than 180 days (Maalouf et al., 2011). Studies using FISH- fluorescence in situ hybridization- painting revealed that HZE particles frequently induce highly complex chromosomal rearrangements when compared with the effect of low-LET IR (George et al., 2013). Carcinogenesis is a major concern for future space missions, as the missions will probably be for longer durations and the longer one is exposed to radiation, the more dangerous it becomes. The astronauts on such missions will be constantly exposed to IR from natural radiation sources. HZE-charged particles are part of the radiation field in space and as it is carcinogenic, HZE particle irradiation promotes more aggressive cancers, such as increased growth rate, transcriptomic signatures, and metastasis (Barcellos-Hoff and Mao, 2016).

    Aside from the risk of cancer that space radiation causes, NASA began focusing on the risk to the astronauts’ Central Nervous System (CNS). Although the brain is largely a radioresistant organ, ground-based animal studies have indicated that space radiation alters neuronal tissue and neuronal functions such as excitability, synaptic transmission, and plasticity. HZE particles have also been demonstrated to inhibit neuronal connectivity, neuronal proliferation, neuronal differentiation and to change glial characterization (Cekanaviciute et al., 2018). However, the long-term effects of higher-dose-rate exposure to radiation are unknown as researchers only observed the response to short-term higher-dose-rate exposure to radiation.

    In conclusion, radiation is very damaging to human beings’ DNA. Normally, one is not as exposed as our Earth has a protective magnetic field that keeps extremely damaging radiation away from us. However, astronauts go past that protective barrier and are exposed to that damaging radiation. The results are a more intensely damaged DNA that is harder to repair. This leads to life-threatening diseases such as aggressive cancers, and also affects the Central Nervous System which consists of the spinal cord and the brain — which is the body’s most complex organ. All in all, we must be extremely grateful to the women and men who put their lives at risk so that they can help keep our Earth healthy and safe by studying it from a different angle.


    Author information

    Affiliations

    London Centre for Nanotechnology, University College, London, UK

    Archana Bhartiya, Mohammed Yusuf & Ian K. Robinson

    Department of Chemistry, University College, London, UK

    Research Complex at Harwell, Harwell Campus, Didcot, UK

    Archana Bhartiya, Stanley Botchway, Mohammed Yusuf & Ian K. Robinson

    Diamond Light Source, Harwell Campus, Didcot, UK

    Darren Batey, Silvia Cipiccia, Xiaowen Shi & Christoph Rau

    Department of Physics, New Mexico State University, Las Cruces, NM, 88003, USA

    Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan

    Condensed Matter Physics and Materials Science Division, Brookhaven National Lab, Upton, NY, 11973, USA



Comments:

  1. Walford

    Fascinating topic

  2. Jaykob

    In my opinion, you admit the mistake.

  3. Hrypanleah

    Really and as I have not thought about this before

  4. Odo

    Good day! I do not see the terms of use of the information. Is it possible to copy the text you write to your site if you link to this page?



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