Contents 1 Types of DNA Damage 2 Detection and Repair of Damaged DNA 2.1 Types of DNA Repair 2.2 Role of ATR and ATM 2.3 Chk1 and Chk2 Functions 3 p53 role in DNA Damage repair system 3.1 Regulation of p53 3.2 p53 serves as transcription factor for bax and p21 3.3 DDR and p53 Role in Cancer 4 A major problem for life 5 Frequencies 6 Steady-state levels 7 Consequences 8 RAD Genes and the Cell Cycle Response to DNA Damage in Saccharomyces cerevisiae 9 See also 10 References


Types of DNA Damage[edit] Damage to DNA that occurs naturally can result from metabolic or hydrolytic processes. Metabolism releases compounds that damage DNA including reactive oxygen species, reactive nitrogen species, reactive carbonyl species, lipid peroxidation products and alkylating agents, among others, while hydrolysis cleaves chemical bonds in DNA.[8] Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats,[9] as documented below. DNA can be damaged via environmental factors as well. Environmental agents such as UV light, ionizing radiation, and genotoxic chemicals. Replication forks can be stalled due to damaged DNA and double strand breaks are also a form of DNA damage[10].


Detection and Repair of Damaged DNA[edit] In the presence of DNA damage, the cell can either repair the damage or induce cell death if the damage is beyond repair. Most damage can be repaired without trigger the damage response system, however more complex damage activates ATR and ATM, key protein kinases in the damage response system[11]. DNA damage inhibits M-CDKs which are a key component of progression into Mitosis. Types of DNA Repair[edit] Some forms of damage repair included, but are not limited to base excision repair, nucleotide excision repair, and non-homologous end joining. Base excision repair finds small changes in base structure and repairs them. Nucleotide excision repair detects and repairs major modifications that alter the conformation of the double helix.7 Non homologous end joining is one way to repair double strand breaks in DNA. [10] Role of ATR and ATM[edit] In all eukaryotic cells, ATR and ATM are protein kinases that detect DNA damage. They bind to DNA damaged sites and activate Chk1, Chk2, and, in animal cells, p53. Together, these proteins make up the DNA damage response system. Some DNA damage does not require the recruitment of ATR and ATM, it is only difficult and extensive damage that requires ATR and ATM. ATM and ATR are required for NHEJ, HR, ICL repair, and NER, as well as replication fork stability during unperturbed DNA replication and in response to replication blocks[2]. ATR is recruited for different forms of damage such as nucleotide damage, stalled replication forks and double strand breaks. ATM is specifically for the damage response to double strand breaks. The MRN complex (composed of Mre11, Rad50, and Nbs1) form immediately at the site of double strand break. This MRN complex recruits ATM to the site of damage. ATR and ATM phosphorylate various proteins that contribute to the damage repair system. The binding of ATR and ATM to damage sites on DNA lead to the recruitment of Chk1 and Chk2. These protein kinases send damage signals to the cell cycle control system to delay the progression of the cell cycle.[10] Chk1 and Chk2 Functions[edit] Chk1 leads to the production of DNA repair enzymes. Chk2 leads to reversible cell cycle arrest. Chk2 as well as ATR/ATM can activate p53 which leads to permanent cell cycle arrest or apoptosis.


p53 role in DNA Damage repair system[edit] When there is too much damage, apoptosis is triggered in order to protect the organism from potentially harmful cells.7 p53, also known as a tumor suppressor gene, is a major regulatory protein in the DNA damage response system which binds directly to the promoters of its target genes. p53 acts primarily at the G1 checkpoint (controlling the G1 to S transition), where it blocks cell cycle progression[1]. Activation of p53 can trigger cell death or permanent cell cycle arrest. p53 can also activate certain repair pathways such was NER[11].  Regulation of p53[edit] In the absence of DNA damage, p53 is regulated by Mdm2 and constantly degraded. When there is DNA damage, Mdm2 is phosphorylated, most likely caused by ATM. The phosphorylation of Mdm2 leads to a reduction in the activity of Mdm2, thus preventing the degradation of p53. Normal, undamaged cell, usually has low levels of p53 while cells under stress and DNA damage, will have high levels of p53.[10] p53 serves as transcription factor for bax and p21[edit] p53 serves as a transcription factors for both bax, a proapoptotic protein as well as p21, a CDK inhibitor. CDK Inhibitors result in cell cycle arrest. Arresting the cell provides the cell time to repair the damage, and if the damage is irreparable, p53 recruits bax to trigger apoptosis.[11] DDR and p53 Role in Cancer[edit] p53 is a major key player in the growth of cancerous cells. Damaged DNA cells with mutated p53 are at a higher risk of becoming cancerous. Common chemotherapy treatments are genotoxic. These treatments are ineffective in cancer tumor thats have mutated p53 since they do not have a functioning p53 to either arrest or kill the damaged cell.


A major problem for life[edit] One indication that DNA damages are a major problem for life is that DNA repair processes, to cope with DNA damages, have been found in all cellular organisms in which DNA repair has been investigated. For example, in bacteria, a regulatory network aimed at repairing DNA damages (called the SOS response in Escherichia coli) has been found in many bacterial species. E. coli RecA, a key enzyme in the SOS response pathway, is the defining member of a ubiquitous class of DNA strand-exchange proteins that are essential for homologous recombination, a pathway that maintains genomic integrity by repairing broken DNA.[12] Genes homologous to RecA and to other central genes in the SOS response pathway are found in almost all the bacterial genomes sequenced to date, covering a large number of phyla, suggesting both an ancient origin and a widespread occurrence of recombinational repair of DNA damage.[13] Eukaryotic recombinases that are homologues of RecA are also widespread in eukaryotic organisms. For example, in fission yeast and humans, RecA homologues promote duplex-duplex DNA-strand exchange needed for repair of many types of DNA lesions.[14][15] Another indication that DNA damages are a major problem for life is that cells make large investments in DNA repair processes. As pointed out by Hoeijmakers,[5] repairing just one double-strand break could require more than 10,000 ATP molecules, as used in signaling the presence of the damage, the generation of repair foci, and the formation (in humans) of the RAD51 nucleofilament (an intermediate in homologous recombinational repair). (RAD51 is a homologue of bacterial RecA.) If the structural modification occurs during the G1 phase of DNA replication, the G1-S checkpoint arrests or postpones the furtherance of the cell cycle before the product enters the S phase.[16]


Frequencies[edit] The list below shows some frequencies with which new naturally occurring DNA damages arise per day, due to endogenous cellular processes. Oxidative damages Humans, per cell per day 10,000[17] 11,500[18] 2,800[19] specific damages 8-oxoGua, 8-oxodG plus 5-HMUra 2,800[20] specific damages 8-oxoGua, 8-oxodG plus 5-HMUra Rats, per cell per day 74,000[18] 86,000[21] 100,000[17] Mice, per cell per day 34,000[19] specific damages 8-oxoGua, 8-oxodG plus 5-HMUra 47,000[22] specific damages oxo8dG in mouse liver 28,000[20] specific damages 8-oxoGua, 8-oxodG, 5-HMUra Depurinations Mammalian cells, per cell per day 2,000 to 10,000[23][24] 9,000[25] 12,000[26] 13,920[27] Depyrimidinations Mammalian cells, per cell per day 600[26] 696[27] Single-strand breaks Mammalian cells, per cell per day 55,200[27] Double-strand breaks Human cells, per cell cycle 10[28] 50[29] O6-methylguanines Mammalian cells, per cell per day 3,120[27] Cytosine deamination Mammalian cells, per cell per day 192[27] Another important endogenous DNA damage is M1dG, short for (3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one). The excretion in urine (likely reflecting rate of occurrence) of M1dG may be as much as 1,000-fold lower than that of 8-oxodG.[30] However, a more important measure may be the steady-state level in DNA, reflecting both rate of occurrence and rate of DNA repair. The steady-state level of M1dG is higher than that of 8-oxodG.[31] This points out that some DNA damages produced at a low rate may be difficult to repair and remain in DNA at a high steady-state level. Both M1dG[32] and 8-oxodG[33] are mutagenic.


Steady-state levels[edit] Steady-state levels of DNA damages represent the balance between formation and repair. More than 100 types of oxidative DNA damage have been characterized, and 8-oxodG constitutes about 5% of the steady state oxidative damages in DNA.[34] Helbock et al.[35] estimated that there were 24,000 steady state oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats. This reflects the accumulation of DNA damage with age. DNA damage accumulation with age is further described in DNA damage theory of aging. Swenberg et al.[36] measured average amounts of selected steady state endogenous DNA damages in mammalian cells. The seven most common damages they evaluated are shown in Table 1. Table 1. Steady-state amounts of endogenous DNA damages Endogenous lesions Number per cell Abasic sites 30,000 N7-(2-hydroxethyl)guanine (7HEG) 3,000 8-hydroxyguanine 2,400 7-(2-oxoethyl)guanine 1,500 Formaldehyde adducts 960 Acrolein-deoxyguanine 120 Malondialdehyde-deoxyguanine 60 Evaluating steady-state damages in specific tissues of the rat, Nakamura and Swenberg[37] indicated that the number of abasic sites varied from about 50,000 per cell in liver, kidney and lung to about 200,000 per cell in the brain.


Consequences[edit] Differentiated somatic cells of adult mammals generally replicate infrequently or not at all. Such cells, including, for example, brain neurons and muscle myocytes, have little or no cell turnover. Non-replicating cells do not generally generate mutations due to DNA damage-induced errors of replication. These non-replicating cells do not commonly give rise to cancer, but they do accumulate DNA damages with time that likely contribute to aging (see DNA damage theory of aging). In a non-replicating cell, a single-strand break or other type of damage in the transcribed strand of DNA can block RNA polymerase II catalysed transcription.[38] This would interfere with the synthesis of the protein coded for by the gene in which the blockage occurred. Brasnjevic et al.[39] summarized the evidence showing that single-strand breaks accumulate with age in the brain (though accumulation differed in different regions of the brain) and that single-strand breaks are the most frequent steady-state DNA damages in the brain. As discussed above, these accumulated single-strand breaks would be expected to block transcription of genes. Consistent with this, as reviewed by Hetman et al.,[40] 182 genes were identified and shown to have reduced transcription in the brains of individuals older than 72 years, compared to transcription in the brains of those less than 43 years old. When 40 particular proteins were evaluated in a muscle of rats, the majority of the proteins showed significant decreases during aging from 18 months (mature rat) to 30 months (aged rat) of age.[41] Another type of DNA damage, the double strand break, was shown to cause cell death (loss of cells) through apoptosis.[42] This type of DNA damage would not accumulate with age, since once a cell was lost through apoptosis, its double strand damage would be lost with it. Thus, damaged DNA segments undermine the DNA replication machinery because these altered sequences of DNA cannot be utilized as true templates to produce copies of one's genetic material. [43]


RAD Genes and the Cell Cycle Response to DNA Damage in Saccharomyces cerevisiae[edit] When DNA is damaged, the cell responds in various ways to fix the damage and minimize the effects on the cell. One such response, specifically in eukaryotic cells, is to delay cell division—the cell becomes arrested for some time in the G2 phase before progressing through the rest of the cell cycle. Various studies have been conducted to elucidate the purpose of this G2 arrest that is induced by DNA damage. Researchers have found that cells that are prematurely forced out of the delay have lower cell viability and higher rates of damaged chromosomes compared with cells that are able to undergo a full G2 arrest, suggesting that the purpose of the delay is to give the cell time to repair damaged chromosomes before continuing with the cell cycle.[44] This ensures the proper functioning of mitosis. Various species of animals exhibit similar mechanisms of cellular delay in response to DNA damage, which can be caused by exposure to x-irradiation. The budding yeast Saccharomyces cerevisiae has specifically been studied because progression through the cell cycle can be followed via nuclear morphology with ease. By studying Saccharomyces cerevisiae, researchers have been able to learn more about radiation-sensitive (RAD) genes, and the effect that RAD mutations may have on the typical cellular DNA damaged-induced delay response. Specifically, the RAD9 gene plays a crucial role in detecting DNA damage and arresting the cell in G2 until the damage is repaired. Through extensive experiments, researchers have been able to illuminate the role that the RAD genes play in delaying cell division in response to DNA damage. When wild-type, growing cells are exposed to various levels of x-irradiation over a given time frame, and then analyzed with a microcolony assay, differences in the cell cycle response can be observed based on which genes are mutated in the cells. For instance, while unirradiated cells will progress normally through the cell cycle, cells that are exposed to x-irradiation either permanently arrest (become inviable) or delay in the G2 phase before continuing to divide in mitosis, further corroborating the idea that the G2 delay is crucial for DNA repair. However, rad strains, which are deficient in DNA repair, exhibit a markedly different response. For instance, rad52 cells, which cannot repair double-stranded DNA breaks, tend to permanently arrest in G2 when exposed to even very low levels of x-irradiation, and rarely end up progressing through the later stages of the cell cycle. This is because the cells cannot repair DNA damage and thus do not enter mitosis. Various other rad mutants exhibit similar responses when exposed to x-irradiation. However, the rad9 strain exhibits an entirely different effect. These cells fail to delay in the G2 phase when exposed to x-irradiation, and end up progressing through the cell cycle unperturbed, before dying. This suggests that the RAD9 gene, unlike the other RAD genes, plays a crucial role in initiating G2 arrest. To further investigate these findings, the cell cycles of double mutant strains have been analyzed. A mutant rad52 rad9 strain—which is both defective in DNA repair and G2 arrest—fails to undergo cell cycle arrest when exposed to x-irradiation. This suggests that even if DNA damage cannot be repaired, if RAD9 is not present, the cell cycle will not delay. Thus, unrepaired DNA damage is the signal that tells RAD9 to halt division and arrest the cell cycle in G2. Furthermore, there is a dose-dependent response; as the levels of x-irradiation—and subsequent DNA damage—increase, more cells, regardless of the mutations they have, become arrested in G2. Another, and perhaps more helpful way to visualize this effect is to look at photomicroscopy slides. Initially, slides of RAD+ and rad9 haploid cells in the exponential phase of growth show simple, single cells, that are indistinguishable from each other. However, the slides look much different after being exposed to x-irradiation for 10 hours. The RAD+ slides now show RAD+ cells existing primarily as two-budded microcolonies, suggesting that cell division has been arrested. In contrast, the rad9 slides show the rad9 cells existing primarily as 3 to 8 budded colonies, and they appear smaller than the RAD+ cells. This is further evidence that the mutant RAD cells continued to divide and are deficient in G2 arrest. However, there is evidence that although the RAD9 gene is necessary to induce G2 arrest in response to DNA damage, giving the cell time to repair the damage, it does not actually play a direct role in repairing DNA. When rad9 cells are artificially arrested in G2 with MBC, a microtubule poison that prevents cellular division, and then treated with x-irradiation, the cells are able to repair their DNA and eventually progress through the cell cycle, dividing into viable cells. Thus, the RAD9 gene plays no role in actually repairing damaged DNA—it simply senses damaged DNA and responds by delaying cell division. The delay, then, is mediated by a control mechanism, rather than the physical damaged DNA.[45] On the other hand, it is possible that there are backup mechanisms that fill the role of RAD9 when it is not present. In fact, some studies have found that RAD9 does indeed play a critical role in DNA repair. In one study, rad9 mutant and normal cells in the exponential phase of growth were exposed to UV-irradiation and synchronized in specific phases of the cell cycle. After being incubated to permit DNA repair, the extent of pyrimidine dimerization (which is indicative of DNA damage) was assessed using sensitive primer extension techniques. It was found that the removal of DNA photolesions was much less efficient in rad9 mutant cells than normal cells, providing evidence that RAD9 is involved in DNA repair. Thus, the role of RAD9 in repairing DNA damage remains unclear.[46] Regardless, it is clear that RAD9 is necessary to sense DNA damage and halt cell division. RAD9 has been suggested to possess 3’ to 5’ exonuclease activity, which is perhaps why it plays a role in detecting DNA damage. When DNA is damaged, it is hypothesized that RAD9 forms a complex with RAD1 and HUS1, and this complex is recruited to sites of DNA damage. It is in this way that RAD9 is able to exert its effects. Although the function of RAD9 has primarily been studied in the budding yeast Saccharomyces cerevisiae, many of the cell cycle control mechanisms are similar between species. Thus, we can conclude that RAD9 likely plays a critical role in the DNA damage response in humans as well.


See also[edit] Ageing Aging brain AP site Direct DNA damage DNA DNA adduct DNA damage theory of aging DNA repair DNA replication Free radical damage to DNA Homologous recombination Meiosis Mutation Natural competence Origin and function of meiosis Reactive oxygen species


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G1 PhaseG2 PhaseDNA8-Oxo-2'-deoxyguanosineMutationDNA RepairDNA Damage Theory Of AgingDNA ReplicationMutationEpigeneticMetabolismHydrolysisReactive Oxygen SpeciesReactive Nitrogen SpeciesCarbonylLipid PeroxidationAlkylationMitosisCHEK1CHEK2TP53BAX ProteinP21EukaryoteAdenosine TriphosphateDepurinationM1GMutagenDNA Damage Theory Of AgingDNA Damage Theory Of AgingTranscription (genetics)ApoptosisAgeingAging BrainAP SiteDirect DNA DamageDNADNA AdductDNA Damage Theory Of AgingDNA RepairDNA ReplicationFree Radical Damage To DNAHomologous RecombinationMeiosisMutationNatural CompetenceOrigin And Function Of MeiosisReactive Oxygen SpeciesDigital Object IdentifierInternational Standard Serial NumberDigital Object IdentifierInternational Standard Book NumberSpecial:BookSources/9783319246949International Standard Book NumberSpecial:BookSources/978-1604565812PubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierInternational Standard Book NumberSpecial:BookSources/978-953-51-1114-6Digital Object IdentifierInternational Standard Serial NumberPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierInternational Standard Book NumberSpecial:BookSources/9783319246949PubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierInternational Standard Book NumberSpecial:BookSources/088372099XInternational Standard Book NumberSpecial:BookSources/978-0883720998International Standard Book NumberSpecial:BookSources/0442225296International Standard Book NumberSpecial:BookSources/978-0442225292PubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierInternational Standard Book NumberSpecial:BookSources/9783319246949Portal:BiologyPortal:MedicineHelp:CategoryCategory:Cellular ProcessesCategory:DNACategory:DNA RepairCategory:Molecular GeneticsCategory:MutationCategory:SenescenceCategory:Pages Using Div Col Without Cols And Colwidth ParametersCategory:Pages Using Columns-list With Deprecated ParametersDiscussion About Edits From This IP Address [n]A List Of Edits Made From This IP Address [y]View The Content Page [c]Discussion About The Content Page [t]Edit This Page [e]Visit The Main Page [z]Guides To Browsing WikipediaFeatured Content – The Best Of WikipediaFind Background Information On Current EventsLoad A Random Article [x]Guidance On How To Use And Edit WikipediaFind Out About WikipediaAbout The Project, What You Can Do, Where To Find ThingsA List Of Recent Changes In The Wiki [r]List Of All English Wikipedia Pages Containing Links To This Page [j]Recent Changes In Pages Linked From This Page [k]Upload Files [u]A List Of All Special Pages [q]Wikipedia:AboutWikipedia:General Disclaimer



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