DNA repair
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[[Image:brokechromo.jpg|frame|right|DNA damage resulting in multiple broken chromosomes]]
'''DNA repair''' refers to a collection of processes by which a [[cell (biology)|cell]] identifies and corrects damage to the [[DNA]] molecules that encode its [[genome]]. In human cells, both normal [[metabolism|metabolic]] activities and environmental factors such as [[UV]] light and [[Radiation]] can cause DNA damage, resulting in as many as 1 million individual [[molecular lesion]]s per cell per day.<ref name="lodish">Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, p963. WH Freeman: New York, NY. 5th ed.</ref> Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to [[Transcription (genetics)|transcribe]] the [[gene]] that the affected DNA encodes. Other lesions induce potentially harmful [[mutation]]s in the cell's genome, which affect the survival of its daughter cells after it undergoes [[mitosis]]. Consequently, the DNA repair process is constantly active as it responds to damage in the DNA structure.
The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
# an irreversible state of dormancy, known as [[senescence]]
# cell suicide, also known as [[apoptosis]] or [[programmed cell death]]
# unregulated cell division, which can lead to the formation of a [[tumor]] that is [[cancer]]ous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism. Many genes that were initially shown to influence [[lifespan]] have turned out to be involved in DNA damage repair and protection.<ref name="browner">Browner WS, Kahn AJ, Ziv E, Reiner AP, Oshima J, Cawthon RM, Hsueh WC, Cummings SR. (2004). The genetics of human longevity. ''Am J Med'' 117(11):851–60.</ref> Failure to correct molecular lesions in cells that form [[gamete]]s can introduce mutations into the genomes of the offspring and thus influence the rate of [[evolution]].
==DNA damage==
DNA damage, due to environmental factors and normal [[metabolism|metabolic]] processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day.<ref name="lodish" /> While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as [[tumor suppressor gene]]s) can impede a cell's ability to carry out its function and appreciably increase the likelihood of [[tumor]] formation.
The vast majority of DNA damage affects the [[primary structure]] of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike [[protein]]s and [[RNA]], DNA usually lacks [[tertiary structure]] and therefore damage or disturbance does not occur at that level. DNA is, however, [[supercoil]]ed and wound around "packaging" proteins called [[histone]]s (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
=== Sources of damage ===
DNA damage can be subdivided into two main types:
# [[endogenous]] damage such as attack by [[reactive oxygen species]] produced from normal metabolic byproducts (spontaneous mutation), especially the process of [[oxidative deamination]];
# exogenous damage caused by external agents such as
## ultraviolet [UV 200-300[[nanometre|nm]]] [[radiation]] from the sun
## other radiation frequencies, including [[x-ray]]s and [[gamma ray]]s
## [[hydrolysis]] or thermal disruption
## certain [[plant]] [[toxin]]s
## human-made [[mutagen|mutagenic chemicals]], especially [[aromatic]] compounds that act as DNA [[intercalation (chemistry)|intercalating agents]]
## cancer [[chemotherapy]] and [[radiotherapy]]
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a [[back mutation]], for example, through [[gene conversion]]).
===Types of damage===
There are four main types of damage to DNA due to endogenous cellular processes:
# ''[[oxidation]]'' of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
# ''[[alkylation]]'' of bases (usually [[methylation]]), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine
# ''[[hydrolysis]]'' of bases, such as deamination, depurination and depyrimidination.
# ''mismatch'' of bases, due to errors in [[DNA replication]], in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Damage caused by exogenous agents comes in many forms. Some examples are:
# ''[[UV light|UV-B light]]'' causes crosslinking between adjacent cytosine and thymine bases creating ''[[pyrimidine dimers]]''. This is called [[direct DNA damage]].
# ''[[UV light|UV-A light]]'' creates mostly free radicals - especially if [[sunscreen]] penetrated into the skin. The damage caused by free radicals is called [[indirect DNA damage]].
# ''[[Ionizing radiation]]'' such as that created by radioactive decay or in ''[[cosmic rays]]'' causes breaks in DNA strands.
# ''Thermal disruption'' at elevated temperature increases the rate of [[depurination]] (loss of [[purine]] bases from the DNA backbone) and single strand breaks. For example, hydrolytic depurination is seen in the [[thermophilic bacteria]], which grow in [[hot springs]] at 85–250 °C.<ref name="Toshihiro">Toshihiro Ohta, Shin-ichi Tokishita, Kayo Mochizuki, Jun Kawase, Masahide Sakahira and Hideo Yamagata, UV Sensitivity and Mutagenesis of the Extremely Thermophilic Eubacterium Thermus thermophilus HB27, Genes and Environment Vol. 28 (2006), No. 2 p.56–61.</ref> The rate of depurination (300 [[purine]] residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an [[adaptive]] response cannot be ruled out.
# ''Industrial chemicals'' such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and [[Crosslinking of DNA]] just to name a few.
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.
===Nuclear versus mitochondrial DNA damage===
In human cells, and [[eukaryotic]] cells in general, DNA is found in two cellular locations - inside the [[Cell nucleus|nucleus]] and inside the [[mitochondria]]. Nuclear DNA (nDNA) exists as [[chromatin]] during non-replicative stages of the [[cell cycle]] and is condensed into aggregate structures known as [[chromosomes]] during [[cell division]]. In either state the DNA is highly compacted and wound up around bead-like proteins called [[histones]]. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria [[organelles]], exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, [[reactive oxygen species]] (ROS), or [[radical (chemistry)|free radicals]], byproducts of the constant production of [[adenosine triphosphate]] (ATP) via [[oxidative phosphorylation]], create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is [[superoxide dismutase]], which is present in both the mitochondria and [[cytoplasm]] of eukaryotic cells.
===Senescence and apoptosis===
Senescence, an irreversible state in which the cell no longer divides ([[mitosis]]), is a protective response to the shortening of the chromosome ends ([[telomeres]]). The telomeres are long regions of repetitive [[noncoding DNA]] that cap chromosomes and undergo partial degradation each time a cell undergoes division (see [[Hayflick limit]]).<ref name="braig">Braig M, Schmitt CA. (2006) . Oncogene-induced senescence: putting the brakes on tumor development. ''Cancer Res'' 66: 2881–2884.</ref> In contrast, [[G0 phase|quiescence]] is a reversible state of cellular dormancy that is unrelated to genome damage (see [[cell cycle]]). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,<ref name="Lynch">Lynch MD. (2006). How does cellular senescence prevent cancer? ''DNA Cell Biol'' 25(2):69–78.</ref> which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth [[cellular signaling]]. Unregulated cell division can lead to the formation of a tumor (see [[cancer]]), which is potentially lethal to an organism. Therefore the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.
===DNA damage and mutation===
It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and thus they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.
==DNA repair mechanisms==
[[Image:Ssvsds.jpg|frame|right|Single strand and double strand DNA damage]]
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the [[genome]] (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister [[chromatid]] as a template to losslessly recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.
Damage to DNA alters the spatial configuration of the helix and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place. The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the [[cell cycle]] that the cell is in.
===Direct reversal===
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can only occur in one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of [[thymine dimer]]s (a common type of [[cyclobutyl dimer]]) upon irradiation with UV light results in an abnormal covalent bond between adjacent thymidine bases. The [[photoreactivation]] process directly reverses this damage by the action of the enzyme [[photolyase]], whose activation is obligately dependent on energy absorbed from [[electromagnetic spectrum|blue/UV light]] (300–500nm [[wavelength]]) to promote catalysis.<ref name="Sancar">Sancar A. (2003). Structure and function of DNA photolyase and cryptochrome blue-light photoreceptors. ''Chem Rev'' 103(6):2203–37. PMID 12797829 </ref> Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called as [[ogt]]. This is an expensive process because each MGMT molecule can only be used once; that is, the reaction is [[stoichiometric]] rather than [[catalytic]].<ref name="watson">Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. (2004). Molecular Biology of the Gene, ch. 9 and 10. Peason Benjamin Cummings; CSHL Press. 5th ed.</ref> A generalized response to methylating agents in bacteria is known as the [[adaptive response]] and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.<ref name="Volkert">Volkert MR. (1988). Adaptive response of Escherichia coli to alkylation damage''Environ Mol Mutagen'' 11(2):241-55.</ref> The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
===Single strand damage===
[[Image:Uracil base glycosidase.jpg|thumb|250px|left|Structure of the base-excision repair enzyme [[DNA glycosylases|uracil-DNA glycosylase]]. The uracil residue is shown in yellow.]]
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.<ref name="watson" />
#[[Base excision repair]] (BER), which repairs damage to a single nucleotide caused by oxidation, alkylation, hydrolysis, or deamination. The base is removed with glycosylase and ultimately replaced by repair synthesis with DNA ligase.
#[[Nucleotide excision repair]] (NER), which repairs damage affecting longer strands of 2–30 bases. This process recognizes bulky, helix-distorting changes such as [[thymine dimer]]s as well as single-strand breaks (repaired with enzymes such [[UvrABC endonuclease]]). A specialized form of NER known as [[Transcription-Coupled Repair]] (TCR) deploys high-priority NER repair enzymes to genes that are being actively [[transcription (genetics)|transcribed]].
#[[Mismatch repair]] (MMR), which corrects errors of [[DNA replication]] and [[genetic recombination|recombination]] that result in mispaired (but normal, that is non- damaged) nucleotides following DNA replication.<br style="clear:both" />
===Double-strand breaks===
Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Two mechanisms exist to repair DSBs: [[non-homologous end joining]] (NHEJ) and [[genetic recombination|recombinational repair]] (also known as template-assisted repair or homologous recombination repair).<ref name="watson" />
[[Image:DNA Repair.jpg|thumb|230px|DNA ligase, shown above repairing chromosomal damage, is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide [[ester]] bond between the phosphate backbone and the deoxyribose nucleotides.]]
In NHEJ, [[DNA Ligase IV]], a specialized [[DNA Ligase]] that forms a complex with the cofactor [[XRCC4]], directly joins the two ends.<ref>Wilson, T. E., Grawunder, U., and Lieber, M. R. Yeast DNA ligase IV mediates non-homologous DNA end joining. (1997) Nature 388, 495–498. PMID 9242411</ref> To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.<ref name="Moore and Haber">Moore JK, Haber JE. Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol. 1996 May;16(5):2164–73. PMID 8628283</ref><ref>Boulton SJ, Jackson SP. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 1996 Sep 16;15(18):5093-103. PMID 8890183</ref><ref name="Wilson and Lieber">Wilson, T. E., and Lieber, M. R. Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase beta (Pol4)-dependent pathway. (1999) J. Biol. Chem. 274, 23599–23609. PMID 10438542</ref><ref>Budman J, Chu G. Processing of DNA for nonhomologous end-joining by cell-free extract. EMBO J. 2005 Feb 23;24(4):849-60. PMID: 15692565</ref> NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher [[eukaryote]]s.<ref name="wang">Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G. (2003). Biochemical evidence for Ku-independent backup pathways of NHEJ. ''Nucleic Acids Res'' 31(18):5377–88.</ref> Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during [[V(D)J recombination]], the process that generates diversity in [[B-cell receptor|B-cell]] and [[T-cell receptor]]s in the [[vertebrate]] [[immune system]].<ref>Jung D, Alt FW. Unraveling V(D)J recombination; insights into gene regulation. Cell. 2004 Jan 23;116(2):299–311. Review. PMID: 14744439</ref>
Recombinational repair requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for [[chromosomal crossover]] during meiosis. This pathway allows a damaged chromosome to be repaired using a sister [[chromatid]] (available in G2 after [[DNA replication]]) or a [[homologous chromosome]] as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the [[replication fork]] and are typically repaired by recombination.
[[Topoisomerase]]s introduce both single- and double-strand breaks in the course of changing the DNA's state of [[supercoil]]ing, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
A team of French researchers bombarded ''[[Deinococcus radiodurans]]'' to study the mechanism of double-strand break DNA repair in that organism. At least two copies of the genome, with random DNA breaks, can form DNA fragments through [[Annealing (biology)|annealing]]. Partially overlapping fragments are then used for synthesis of [[Homology (biology)#Homology of sequences in genetics|homologous]] regions through a moving [[D-loop]] that can continue extension until they find [[complementary]] partner strands. In the final step there is [[Chromosomal crossover|crossover]] by means of [[RecA]]-dependent [[Chromosomal crossover|homologous recombination]].<ref name="MRadman">{{cite journal | author=Zahradka K, Slade D, Bailone A, Sommer S, Averbeck D, Petranovic M, Lindner AB, Radman M | title=Reassembly of shattered chromosomes in Deinococcus radiodurans | journal=NATURE | volume=443 | issue=7111 | year=2006 | pages=569–573 | pmid=17006450 | doi=10.1038/nature05160}}</ref>
===Translesion synthesis===
Translesion synthesis is a DNA damage tolerance process that allows the [[DNA replication]] machinery to replicate past DNA lesions such as [[thymine dimer]]s or [[AP site]]s. It involves the switching out of regular [[DNA polymerase]]s for specialized translesion polymerases, often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication [[processivity]] factor [[PCNA]]. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, [[DNA polymerase eta|Pol η]] mediates error-free bypass of lesions induced by [[ultraviolet|UV irradiation]], whereas Pol ζ introduces mutations at these sites. From a cellular perspective, risking the introduction of [[point mutation]]s during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death.
==Global response to DNA damage==
Cells exposed to [[ionizing radiation]], [[ultraviolet light]] or chemicals are prone to acquire multiple sites of bulky DNA lesions and double strand breaks. Moreover, DNA damaging agents can damage other [[biomolecule]]s such as [[protein]]s, [[carbohydrate]]s, [[lipid]]s and [[RNA]]. The accumulation of damage, specifically double strand breaks or adducts stalling the [[replication fork]]s, are among known stimulation signals for a global response to DNA damage.<ref name="textbook">Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T. (2006). DNA Repair and Mutagenesis, part 3. ASM Press. 2nd ed.</ref> The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance or [[apoptosis]]. The common features of global response are induction of multiple [[gene]]s, [[cell cycle]] arrest, and inhibition of [[cell division]].
===DNA damage checkpoints===
After DNA damage, [[cell cycle]] [[cell cycle checkpoint|checkpoints]] are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the [[G1 phase|G1]]/[[S phase|S]] and [[G2 phase|G2]]/[[mitosis|M]] boundaries. An intra-[[S phase|S]] checkpoint also exists. Checkpoint activation is controlled by two master [[kinase]]s, [[ataxia telangiectasia mutated|ATM]] and [[Ataxia Telangiectasia and Rad3 related|ATR]]. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,<ref>Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003 Jan 30;421(6922):499–506.</ref> whereas ATR primarily responds to stalled [[replication fork]]s. These kinases [[phosphorylation|phosphorylate]] downstream targets in a [[signal transduction]] cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including [[BRCA1]], [[MDC1]], and [[53BP1]] has also been identified.<ref>{{cite book |title=DNA Repair, Genetic Instability, and Cancer |last=Wei |first=Qingyi |coauthors=Lei Li, David Chen |year=2007 |publisher=World Scientific |isbn=9812700145 }}</ref> These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
[[p53]] is an important downstream target of ATM and ATR, as it is required for inducing [[apoptosis]] following DNA damage.<ref>{{cite book |title=Checkpoint Controls and Cancer |last=Schonthal |first=Axel H. |year=2004 |publisher=Humana Press |isbn=1588295001 }}</ref> At the G1/S checkpoint, p53 functions by deactivating the [[CDK2]]/[[cyclin E]] complex. Similarly, [[p21]] mediates the G2/M checkpoint by deactivating the [[CDK1]]/[[cyclin B]] complex.
===The prokaryotic SOS response===
The [[SOS response]] is the term used to describe changes in [[gene expression]] in ''[[Escherichia coli]]'' and other bacteria in response to extensive DNA damage. The [[prokaryotic]] SOS system is regulated by two key proteins: [[LexA]] and [[RecA]]. The LexA [[homodimer]] is a [[Transcription (genetics)|transcription]]al [[repressor]] that binds to [[operator]] sequences commonly referred to as SOS boxes. It is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.<ref name="Janion"> Janion C. (2001). Some aspects of the SOS response system-a critical survey. Acta Biochim Pol. 48(3):599–610</ref>
The most common cellular signals activating the SOS response are regions of single stranded DNA (ssDNA), arising from stalled [[replication fork]]s or double strand breaks, which are processed by [[DNA helicase]] to separate the two DNA strands.<ref name="textbook"> In the initiation step, RecA protein binds to ssDNA in an [[ATP hydrolysis]] driven reaction creating RecA–ssDNA filaments. RecA–ssDNA filaments activate LexA auto[[protease]] activity which ultimately leads to cleavage of LexA dimmer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.
SOS boxes are 20-nucleotide long sequences near promoters with [[palindromic]] structure and a high degree of sequence conservation. This distinction in promoter sequences causes differential binding of LexA to different promoters and allows for timing of the SOS response. Logically, the lesion repair genes are induced at the beginning of SOS response. The error prone translession polymerases, for example: UmuCD’2 (also called DNA polymerase V), are induced later on as a last resort.<ref name="Goodman"> Schlacher K, Pham P, Cox MM, and Goodman MF. (2006). Roles of DNA Polymerase V and RecA Protein in SOS Damage-Induced Mutation. Chem. Rev 106(2) pp 406–419</ref> Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer which subsequently binds to the SOS boxes near promoters and restores normal gene expression.
===Eukaryotic transcriptional responses to DNA damage===
[[Eukaryotic]] cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, [[cell cycle checkpoint]] control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of [[yeast]] ''[[Saccharomyces cerevisiae]]'' to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental [[shock response]] indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the [[heterogeneity]] of [[mammalian]] cells. In an animal different types of cells are distributed amongst different organs which have evolved different sensitivities to DNA damage.<ref name="Goodman"> Fry RC, Begley TJ, Samson LD. (2004). Genome-wide responses to DNA-damaging agents. Annu Rev Microbiol. 59 pp 357–77</ref>
In general global response to DNA damage involves expression of multiple genes responsible for [[postreplication repair]], homologous recombination, nucleotide excision repair, [[DNA damage checkpoint]], global transcriptional activation, genes controlling mRNA decay and many others. The vast amount of damage to a cell leaves it with an important decision; undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival which will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of [Y family translesion DNA [[polymerase]]s present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.<ref name="textbook" />
==DNA repair and aging==
===Pathological effects of poor DNA repair===
[[Image:Dnarepair1.jpg|frame|DNA repair rate is an important determinant of cell pathology]]
Experimental animals with genetic deficiencies in DNA repair often show decreased lifespan and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get [[lymphoma]] and infections more often, and consequently have shorter lifespans than wild-type mice.<ref name="espejel">Espejel S, Martin M, Klatt P, Martin-Caballero J, Flores JM, Blasco MA. (2004). Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice. ''EMBO Rep'' 5(5):503–9.</ref> Similarly, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.<ref name="deboer">de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GT, van Leeuwen W, Themmen AP, Meradji M, Hoeijmakers JH. (2002). Premature aging in mice deficient in DNA repair and transcription. ''Science'' 296(5571):1276–9.</ref> However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened lifespan without correspondingly higher rates of mutation.<ref name="dolle">Dolle ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J. (2006). Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. ''[[Mutation Research]]'' 596(1-2):22–35.</ref>
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk (see [[DNA repair#Medicine and DNA repair modulation|below]]). On the other hand, organisms with enhanced DNA repair systems, such as ''[[Deinococcus radiodurans]]'', the most radiation-resistant known organism, exhibit remarkable resistance to the double strand break-inducing effects of [[radioactivity]], likely due to enhanced efficiency of DNA repair and especially NHEJ.<ref name="kobayashi">Kobayashi Y, Narumi I, Satoh K, Funayama T, Kikuchi M, Kitayama S, Watanabe H. (2004). Radiation response mechanisms of the extremely radioresistant bacterium Deinococcus radiodurans.''Biol Sci Space'' 18(3):134–5.</ref> Some claim that if a DNA damage event occurs during the self-repair process then the combination of the two events will exert an effect greater than the sum of the individual events (eg, if they occurred with a long time delay between them), this is the basis of the ''second event theory''. {{Fact|date=June 2008}}
===Longevity and caloric restriction===
[[Image:Dnadamage.jpg|frame|right|Most lifespan influencing genes affect the rate of DNA damage]]
A number of individual genes have been identified as influencing variations in lifespan within a population of organisms. The effects of these genes is strongly dependent on the environment, particularly on the organism's diet. [[Caloric restriction]] reproducibly results in extended lifespan in a variety of organisms, likely via [[nutrient sensing]] pathways and decreased [[metabolic rate]]. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see<ref name="spindler">Spindler SR. (2005). Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. ''Mech Ageing Dev'' 126(9):960–6.</ref> for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.
For example, increasing the [[gene dosage]] of the gene SIR-2, which regulates DNA packaging in the [[nematode worm]] ''Caenorhabditis elegans'', can significantly extend lifespan.<ref name="tissenbaum">Tissenbaum HA, Guarente L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. ''Nature'' 410(6825):227–30.</ref> The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.<ref name="cohen">Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. ''Science'' 305(5682):390–2.</ref> Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,<ref name="cabelof">Cabelof DC, Yanamadala S, Raffoul JJ, Guo Z, Soofi A, Heydari AR. (2003). Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline. ''DNA Repair (Amst.)'' 2(3):295–307.</ref> although similar effects have not been observed in mitochondrial DNA.<ref name="stuart">Stuart JA, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA. (2004). Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction. ''FASEB J'' 18(3):595–7.</ref>
Interestingly, the ''C. elegans'' gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended lifespan under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.<ref name="walker">Walker DW, McColl G, Jenkins NL, Harris J, Lithgow GJ. (2000). Evolution of lifespan in C. elegans. ''Nature'' 405(6784):296–7.</ref> This observation supports the [[pleiotropy]] theory of the [[senescence#theories of aging|biological origins of aging]], which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.
==Medicine and DNA repair modulation==
===Hereditary DNA repair disorders===
Defects in the NER mechanism are responsible for several genetic disorders, including:
* [[xeroderma pigmentosum]]: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
* [[Cockayne syndrome]]: hypersensitivity to UV and chemical agents
* [[trichothiodystrophy]]: sensitive skin, brittle hair and nails
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.
Other DNA repair disorders include:
* [[Werner's syndrome]]: premature aging and retarded growth
* [[Bloom syndrome|Bloom's syndrome]]: sunlight hypersensitivity, high incidence of [[malignant|malignancies]] (especially [[leukemia]]s).
* [[ataxia telangiectasia]]: sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental [[progeria]]s" ("[[accelerated aging disease]]s") because their victims appear elderly and suffer from aging-related diseases at an abnormally young age.
Other diseases associated with reduced DNA repair function include [[Fanconi's anemia]], hereditary [[breast cancer]] and hereditary [[colon cancer]].
===DNA repair and cancer===
Inherited mutations that affect DNA repair genes are strongly associated with high cancer risks in humans. [[Hereditary nonpolyposis colorectal cancer]] (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. [[BRCA1]] and [[BRCA2]], two famous mutations conferring a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.
Cancer therapy procedures such as [[chemotherapy]] and [[radiotherapy]] work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing - most typically cancer cells - are preferentially affected. The side effect is that other non-cancerous but rapidly dividing cells such as [[stem cell]]s in the bone marrow are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).
==DNA repair and evolution==
The basic processes of DNA repair are highly [[conservation (genetics)|conserved]] among both [[prokaryotes]] and [[eukaryotes]] and even among [[bacteriophage]] ([[virus]]es that infect [[bacteria]]); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.<ref name="Cromie">Cromie GA, Connelly JC, Leach DR (2001). Recombination at double-strand breaks and DNA ends: conserved mechanisms from phage to humans. ''Mol Cell.'' 8(6):1163–74.</ref> The ability of a large number of protein [[structural motif]]s to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.<ref name="obrien">O'Brien PJ. (2006). Catalytic promiscuity and the divergent evolution of DNA repair enzymes. ''Chem Rev'' 106(2):720–52.</ref>
The [[fossil record]] indicates that single celled life began to proliferate on the planet at some point during the [[Precambrian]] period, although exactly when recognizably modern life first emerged is unclear. [[Nucleic acid]]s became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "[[oxygen catastrophe]]") due to [[photosynthesis|photosynthetic]] organisms, as well as the presence of potentially damaging [[free radical]]s in the cell due to [[oxidative phosphorylation]], necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by [[oxidative stress]].
===Rate of evolutionary change===
On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism which results in a change from the original sequence. When this occurs, [[mutation]]s may propagate into the genomes of the cell's progeny. Should such an event occur in a [[germ line]] cell that will eventually produce a [[gamete]], the mutation has the potential to be passed on to the organism's offspring. The rate of [[evolution]] in a particular species (or, more narrowly, in a particular gene) is a function of the rate of mutation. Consequently, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change.<ref name="Maresca">Maresca B, Schwartz JH (2006). Sudden origins: a general mechanism of evolution based on stress protein concentration and rapid environmental change. ''Anat Rec B New Anat.'' Jan;289(1):38–46</ref>
==See also==
<div class="references-small" style="-moz-column-count:3; column-count:3;">
* [[DNA damage theory of aging]]
* [[Accelerated aging disease]]
* [[Aging DNA]]
* [[Cell cycle]]
* [[DNA replication]]
* [[Gene therapy]]
* [[Life extension]]
* [[Human mitochondrial genetics]]
* [[Progeria]]
* [[Senescence]]
* The scientific journal ''DNA Repair'' under [[Mutation Research]]
</div>
== References ==
<div class="references-small" style="column-count:2;-moz-column-count:2;">
<references />
</div>
==External links==
{{Spoken Wikipedia|DNA repair.ogg|2005-06-17}}
*[http://asajj.roswellpark.org/huberman/DNA_Repair/DNA_Repair.htm Roswell Park Cancer Institute DNA Repair Lectures]
*[http://whyweage.com/node/20 DNA Repair - A summary of the primary mechanisms]
*[http://www.cgal.icnet.uk/DNA_Repair_Genes.html A comprehensive list of Human DNA Repair Genes]
*[http://www.biochem.ucl.ac.uk/bsm/xtal/teach/repair/tibs3.html 3D structures of some DNA repair enzymes]
*[http://www.scielo.br/scielo.php?pid=S0100-84551997000400032&script=sci_arttext&tlng=en Human DNA repair diseases]
*[http://tango01.cit.nih.gov/sig/home.taf?_function=main&SIGInfo_SIGID=32 DNA repair special interest group]
*[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html DNA Repair]
*[http://www.benbest.com/lifeext/aging.html#dna DNA Damage and DNA Repair]
*[http://www.benbest.com/lifeext/aging.html#progeria Segmental Progeria]
{{featured article}}
[[Category:Aging]]
[[Category:Cellular processes]]
[[Category:Gerontology]]
[[Category:Molecular genetics]]
[[Category:Mutation]]
[[Category:DNA repair| ]]
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