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The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult torepair” lesions such as double‐strand breaks without arepair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus (...) to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinationalrepair that are stimulated by the NPC, and present a model for NPC‐facilitatedrepair. (shrink)

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The recent finding of a role for the recA gene in DNA replication restart does not negate previous data showing the existence of recA‐dependent recombinational DNArepair, which occurs when there are two DNA duplexes present, as in the case for recA‐dependent excisionrepair, for postreplicationrepair (i.e., therepair of DNA daughter‐strand gaps), and for therepair of DNA double‐strand breaks. Recombinational DNArepair is critical for the survival of damaged cells. BioEssays 26:1322–1326, (...) 2004. © 2004 Wiley Periodicals, Inc. (shrink)

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The major mechanism ofrepair of damage to DNA involves a conceptually simple process of enzymatic excision and resynthesis of small regions of DNA. In man and other mammals, this process is regulated by several gene loci; up to 15 mutually complementary genes or gene products may be involved.Repair deficiency results in an array of clinical symptoms in skin, central nervous system, and hematopoietic and immune systems, the major example being xeroderma pigmentosum (XP), a disease with a (...) high incidence of cancer. Cloningrepair genes by straightforward methods has proved difficult, but we have begun the effort by demonstrating that correction of a humanrepair deficiency can be achieved by transferring very small fragments of DNA from normal hamsters into XP cells. One of the complementation groups of XP cells (group C) appears to express a change in gene regulation such that these cellsrepair only a small clustered region of the DNA with high efficiency. (shrink)

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Therepair of chromosomal double‐strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSBrepair is the RecA/Rad51‐mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template torepair the lesion. Here, in reviewing research about DSBrepair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination mechanisms.

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Eukaryotic cells are able to mount several genetically complex cellular responses to DNA damage. The yeast Saccharomyces cerevisiae is a genetically well characterized organism that is also amenable to molecular and biochemical studies. Hence, this organism has provided a useful and informative model for dissecting the biochemistry and molecular biology of DNArepair in eukaryotes.

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DNArepair is important in such phenomena as carcinogenesis and aging. While much is known about DNArepair in single‐cell systems such as bacteria, yeast, and cultured mammalian cells, it is necessary to examine DNArepair in a developmental context in order to completely understand its processes in complex metazoa such as man. We present data to support the notion that proliferating cells from organ systems, tumors, and embryos have a greater DNArepair capacity than terminally (...) differentiated, nonproliferating cells. Differential expression ofrepair genes and accessibility of chromatin torepair enzymes are considered as determinants in the developmental regulation of DNArepair. (shrink)

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UV‐radiation‐induced lesions in DNA result in the formation of: (1) excision gaps (i.e. a lesion is excised, leaving a gap), (2) daughter‐strand gaps (i.e. a lesion can be skipped during replication, leaving a gap), and (3) double‐strand breaks (i.e. the DNA strand opposite a gap can be cut). In Escherichia coli, the recA gene product is involved in repairs of all three types of lesions –repair of daughter‐strand gaps (2) and double‐strand breaks (3) constitutes post‐replicationrepair. The (...) evidence suggests, furthermore, that recA‐dependentrepair of excision gaps (1) produced in DNA replicated prior to UV irradiation (pre‐replicationrepair) appears to occur by similar mechanisms. (shrink)

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DNA topoisomerases are enzymes that can modify, and may regulate, the topological state of DNA through concerted breaking and rejoining of the DNA strands. They have been believed to be directly involved in DNA excisionrepair, and perhaps to be required for the control ofrepair as well. The vicissitudes of this hypothesis provide a noteworthy example of the dangers of interpreting cellular phenomena without genetic information and vice versa.

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Taking advantage of the fact that they need not replicate their DNA, terminally differentiated neurons onlyrepair their expressed genes and largely dispense with the burden of removing damage from most of their genome. However, they may pay a heavy price for this laxity if unforeseen circumstances, such as a pathological condition like Alzheimer's disease, cause them to re‐enter the cell cycle. The lifetime accumulation of unrepaired lesions in the silent genes of neurons is likely to be significant and (...) may result in aborting the mitotic process and triggering cell death if the cells attempt to express these dormant genes and resume DNA replication. BioEssays 25:168–173, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

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The problem we discuss is whether mammalian cells possess genes whose expression is specifically enhanced by DNA damage in order to cope with the damage. The paradigm is the SOS response in E. coli. We conclude that there is compelling evidence that DNA‐damaging agents do affect gene expression, and that mutation frequencies are increased, but proof that arepair process per se is induced remains elusive. We offer here the hypothesis that recognition of the presence of DNA damage by (...) poly(ADPribose) polymerase effects preprogrammed changes in gene expression. (shrink)

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In this review, we discuss a novel on‐site remodeling function that is mediated by the H2A‐ubiquitin binding protein ZRF1. ZRF1 facilitates the remodeling of multiprotein complexes at chromatin and lies at the heart of signaling processes that occur at DNA damage sites and during transcriptional activation. In nucleotide excisionrepair ZRF1 remodels E3 ubiquitin ligase complexes at the damage site. During embryonic stem cell differentiation, it contributes to retinoic acid‐mediated gene activation by altering the subunit composition of the Mediator (...) complex. We postulate that ZRF1 operates in conjunction with cellular remodeling machines and suggest that on‐site remodeling might be a hallmark of many chromatin‐associated signaling pathways. We discuss yet unexplored functions of ZRF1‐mediated remodeling in replication and double strand breakrepair. In conclusion, we postulate that on‐site remodeling of multiprotein complexes is essential for the timing of chromatin signaling processes. (shrink)

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Recently discovered transcription‐independent features of p53 involve the choice of DNA damagerepair pathway after PARylation, and p53's complex formation with phosphoinositide lipids, PI(4,5)P2. PARylation‐mediated rapid accumulation of p53 at DNA damage sites is linked to the recruitment of downstreamrepair factors and tumor suppression. This links p53's capability to sense damaged DNA in vitro and its relevant functions in cells. Further, PI(4,5)P2 rapidly accumulates at damage sites like p53 and complexes with p53, while it is required for (...) ATR recruitment. These findings help explain how p53 and PI(4,5)P2 maintain genome stability by directing DNArepair pathway choice. Additionally, there is a strong correlation between p53 sequence homology, genome mutation rates as well as lifespans across various mammalian species. Further investigation is required to better understand the connections between genome stability, tumor suppression, longevity and the transcriptional‐independent function of p53. (shrink)

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As recently as six years ago, three human diseases with similar phenotypes were mistakenly believed to be caused by a single genetic defect. The three diseases, Ataxia-telangiectasia, Nijmegen breakage syndrome, and an AT-like disorder are now known, however, to have defects in three separate genes: ATM, NBS1, and MRE11. Furthermore, new recent studies have shown now that all three gene products interact; the ATM kinase phosphorylates NBS1,1 which, in turn, associates with MRE11 to regulate DNArepair. Remarkably or expectedly, (...) depending on one's point of view, the similarity in disease phenotypes is evidently due to defects in a common DNArepair pathway. BioEssays 22:966–969, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

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Cockayne syndrome is a rare autosomal recessive disease characterized by a complex clinical phenotype. Most Cockayne syndrome cells are hypersensitive to killing by ultraviolet radiation. This observation has prompted a wealth of studies on the DNArepair capacity of Cockayne syndrome cells in vitro. Many studies support the notion that such cells are defective in a DNArepair mode(s) that is transcription‐dependent. However, it remains to be established that this is a primary molecular defect in Cockayne syndrome cells (...) and that it explains the complex clinical phenotype associated with the disease. An alternative hypothesis is that Cockayne syndrome cells have a defect in transcription affecting the expression of certain genes, which is compatible with embryogenesis but not with normal post‐natal development. Defective transcription may impair the normal processing of DNA damage during transcription‐dependentrepair.‘“Curiouser and curiouser” cried Alice.’ (Lewis Carroll, Alice's Adventures in Wonderland). (shrink)

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Cells fine‐tune their DNArepair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV‐induced pyrimidine dimers in mammalian cells,repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapidrepair, and torepair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Somerepair‐defective diseases (...) may involverepair‐transcription coupling: three candidate genes have been suggested.However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription.Repair of other damage departs further from the paradigm, even in some UV‐mimetic lesions. No selectivity is known forrepair of the very frequent minor forms of base damage. And the most interesting consequence of selectiverepair, selective mutagenesis, normally occurs for UV‐induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UVrepair should be resisted. (shrink)

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Poly(ADP‐ribosyl)ation is a post‐translational modification occurring in the nucleus. The most abundant and best‐characterized enzyme catalyzing this reaction, poly(ADP‐ribose) polymerase 1 (PARP1), participates in fundamental nuclear events. The enzyme functions as molecular “nick sensor”. It binds with high affinity to DNA single‐strand breaks resulting in the initiation of its catalytic activity. Activated PARP1 promotes base excisionrepair. In addition, PARP1 modifies several transcription factors and thereby precludes their binding to DNA. We propose that a major function of PARP1 includes (...) the silencing of transcription preventing expression of damaged genes. Concomitant stimulation of DNArepair suggests that PARP1 acts as a switch between transcription and DNArepair. Another PARP‐type enzyme, tankyrase, is involved in the regulation of telomere elongation. Tankyrase modifies a telomere‐associated protein and thereby prevents it masking telomeric repeats providing access of telomerase for telomere elongation. Therefore, poly(ADP‐ribosyl)ation reactions may act as molecular switches in DNA metabolism. BioEssays 23:543–548, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

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The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNArepair. Indeed, KDM5A engages poly(ADP‐ribose) (PAR) chains at damage sites through a previously uncharacterized coiled‐coil domain, a novel binding mode for PAR interactions. While KDM5A is a well‐known transcriptional regulator, its function in DNArepair is only now emerging. Here we review the molecular mechanisms that regulate this PARP1‐macroH2A1.2‐KDM5A axis in DNA damage and consider the potential involvement of this pathway (...) in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA‐based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies. (shrink)

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The identification of cellular deficiences in the ability torepair damage in DNA in individuals with several cancer‐prone genetic disorders, has led to the idea that defective DNArepair results in cancer. In patients with trichothiodystrophy, however, a recently discovered defect in therepair of ultraviolet damage in DNA is not associated with cancer‐proneness. Thus our previous ideas about the connections between DNArepair capacity and cancer susceptibility need to be reevaluated.

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Endo‐exonucleases from E. coli to man, although very different proteins, are multifunctional enzymes with similar enzymatic activities. They probably have two common but opposing biological roles. On the one hand, they promote survival of the organism by acting in recombination and recombinational DNArepair to diversify and help preserve the genome intact. On the other hand, they degrade the genomic DNA when it is damaged beyondrepair. This ensures elimination of heavily mutagenized cells from the population.

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Transcription is a fundamental cellular process and the first step in gene regulation. Although RNA polymerase (RNAP) is highly processive, in growing cells the progression of transcription can be hindered by obstacles on the DNA template, such as damaged DNA. The authors recent findings highlight a trade‐off between transcription fidelity and DNA breakrepair. While a lot of work has focused on the interaction between transcription and nucleotide excisionrepair, less is known about how transcription influences the (...) class='Hi'>repair of DNA breaks. The authors suggest that when the cell experiences stress from DNA breaks, the control of RNAP processivity affects the balance between preserving transcription integrity and DNArepair. Here, how the conflict between transcription and DNA double‐strand break (DSB)repair threatens the integrity of both RNA and DNA are discussed. In reviewing this field, the authors speculate on cellular paradigms where this equilibrium is well sustained, and instances where the maintenance of transcription fidelity is favored over genome stability. (shrink)

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The RAD6 pathway of budding yeast, Saccharomyces cerevisiae, is responsible for a substantial fraction of this organism's resistance to DNA damage, and also for induced mutagenesis. The pathway appears to incorporate two different recovery processes, both regulated by RAD6. The error‐prone recovery prcess accounts for only a small amount of RAD6‐dependent resistance, but probably all induced mutagenesis. The underlying mechanism, for error‐prone recovery is very likely to be translesion synthesis. The error‐free recovery process accounts for most of RAD6‐dependent resistace, but (...) its mechanism is less clear; it may entail error‐free bypass by template switching and/or DNA gap filling by recombination. RAD6 regulates these activities by ubiquitinateins, and the roles they play in error‐free and error‐prone recovery, have not yet been established. (shrink)

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The proteins that are implicated in the basal transcription of protein coding genes have now been identified. Although little is known about their function, recent data demonstrate the ability of these proteins, previously called class II transcription factors, to participate in other reactions: TBP, the TATA‐box binding factor, is involved in class I and III transcription, while TFIIH has been shown to possess components that are involved in the DNArepair mechanism. The involvement of some if not all of (...) the TFIIH subunits in transcription andrepair may explain the heterogeneity of the various and sometimes completely unrelated symptoms observed in xeroderma pigmentosum, Cockayne Syndrome and trichothiodystrophy disorders. (shrink)

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ArgumentThis paper brings together the history of risk and the history of DNArepair, a biological phenomenon that emerged as a research field in between molecular biology, genetics, and radiation research in the 1960s. The case of xeroderma pigmentosum (XP), an inherited hypersensitivity to UV light and, hence, a disposition to skin cancer will be the starting point to argue that, in the 1970s and 1980s, DNArepair became entangled in the creation of new models of the human (...) body at risk – what is here conceptually referred to as the vulnerability aspect of body history – and new attempts at cancer prevention and enhancement of the body associated with the new flourishing research areas of antimutagenesis and anticarcinogenesis. The aim will be to demonstrate that DNArepair created special attempts at disease prevention: molecular enhancement, seeking to identify means to increase the self-repair abilities of the body at the molecular level. Prevention in this sense meant enhancing the body's ability to cope with the environmental hazards of an already toxic world. This strategy has recently been adopted by the beauty industry, which introduced DNA care as a new target for skin care research and anti-aging formulas. (shrink)

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During the evolution of aerobic life, antioxidant defence systems developed that either directly prevent oxidative modifications of the cellular constituents or remove the modified components. An example of the latter is the proteasome, which removes cytosolic oxidised proteins. Recently, a novel mechanism of activation of the nuclear 20S proteasome was discovered: automodified poly‐(ADP‐ribose) polymerase‐1 (PARP‐1) activates the proteasome to facilitate selective degradation of oxidatively damaged histones. Since activation of the PARP‐1 itself is induced by DNA damage and is supposed to (...) play a role in DNArepair, these new results suggest a joint role of PARP‐1 in the removal of oxidised nucleoproteins and in DNArepair. We hypothesise that PARP‐1 could provide a co‐ordinative link between two nuclear antioxidant defence systems, whose concerted activation would produce a fast and efficient restoration of the native chromatin structure following oxidative stress. BioEssays 24:1060–1065, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

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Several DNA-damage detection andrepair mechanisms have evolved torepair double-strand breaks induced by mutagens. Later in evolutionary history, DNA single- and double-strand cuts made possible immune diversity by V(D)J recombination and recombination at meiosis. Such cuts are induced endogenously and are highly regulated and controlled. In meiosis, DNA cuts are essential for the initiation of homologous recombination, and for the formation of joint molecule and crossovers. Many proteins that function during somatic DNA-damage detection andrepair are (...) also active during homologous recombination. However, their meiotic functions may be altered from their somatic roles through localization, posttranslational modifications and/or interactions with meiosis-specific proteins. Presumably, somaticrepair functions and meiotic recombination diverged during evolution, resulting in adaptations specific to sexual reproduction. BioEssays 27:795–808, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

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Cohesin establishes sister‐chromatid cohesion during S phase to ensure proper chromosome segregation in mitosis. It also facilitates postreplicative homologous recombinationrepair of DNA double‐strand breaks by promoting local pairing of damaged and intact sister chromatids. In G2 phase, cohesin that is not bound to chromatin is inactivated, but its reactivation can occur in response to DNA damage. Recent papers by Koshland's and Sjögren's groups describe the critical role of the known cohesin cofactor Eco1 (Ctf7) and ATR checkpoint kinase in (...) damage‐induced reactivation of cohesin, revealing an intricate mechanism that regulates sister‐chromatid pairing to maintain genome integrity.1,2 BioEssays 30:5–9, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

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Human severe combined immune deficiency (SCID) is the most serious inherited immunological deficit. Recent work has revealed defects in the predominant pathway for double‐strand breakrepair called nonhomologous DNA end joining, or NHEJ. Progress in the biochemistry and genetics of NHEJ and of human SCID has proven to be synergistic between these two fields in a manner that covers the range from biochemical etiology to considerations about possible gene therapy for the B− SCID patients. BioEssays 25:1061–1070, 2003. © 2003 (...) Wiley Periodicals, Inc. (shrink)

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Exposure of man to chemical agents can occur intentionally, as in the treatment of disease, or inadvertently because the environment contains a wide range of synthetic or naturally occurring chemicals. The alkylating agents are a diverse group of compounds (Fig. 1) and comprise a good example of such xenobiotics, since much is known about their occurrence, and their biological effects include carcinogenicity, mutagenicity, toxicity and teratogenicity.Exposure to potentially carcinogenic alkylating agents such as nitrosamines may occur occupationally, from cigarette smoke, from (...) certain foodstuffs and even endogenously through the ingestion of the appropriate precursor chemicals.1 At the other extreme, the cytotoxic effects of agents such as the chloroethylating nitrosamides or mustards have been exploited in the design of certain antitumour drugs.2 The effectiveness of antitumour agents and the other, mostly adverse, biological effects of alkylating agents have been ascribed to their ability to damage cellular macromolecules, in particular DNA. This review concentrates on investigations carried out over the past two years on the role of DNA damage in carcinogenesis, but we shall see how recent advances in this area of research have also led to a better understanding of the mechanisms of the cytotoxic effects of alkylating antitumour agents. (shrink)

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In addition to double‐ and single‐strand DNA breaks and isolated base modifications, ionizing radiation induces clustered DNA damage, which contains two or more lesions closely spaced within about two helical turns on opposite DNA strands. Post‐irradiationrepair of single‐base lesions is routinely performed by base excisionrepair and a DNA strand break is involved as an intermediate. Simultaneous processing of lesions on opposite DNA strands may generate double‐strand DNA breaks and enhance nonhomologous end joining, which frequently results in (...) the formation of deletions. Recent studies support the possibility that the mechanism of base excisionrepair contributes to genome stability by diminishing the formation of double‐strand DNA breaks during processing of clustered lesions. BioEssays 23:745–749, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

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The many genetic complementation groups of DNA excision‐repair defective mammalian cells indicate the considerable complexity of the excisionrepair process. The cloning of severalrepair genes is taking the field a step closer to mechanistic studies of the actions and interactions ofrepair proteins. Early biochemical studies of mammalian DNArepair in vitro are now at hand.Repair synthesis in damaged DNA can be monitored by following the incorporation of radiolabelled nucleotides. Synthesis is carried (...) out by mammalian cell extracts and is defective in extracts from cell lines derived from individuals with the excisionrepair disorder xeroderma pigmentosum. Biochemical complementation of the defective extracts can be used to purifyrepair proteins.Repair of damage caused by agents including ultraviolet irradiation, psoralens, and platinating compounds has been observed. Neutralising antibodies against the human single‐stranded DNA binding protein (HSSB) have demonstrated a requirement for this protein in DNA excisionrepair as well as in DNA replication. (shrink)

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Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intrastrand base‐pairing. This intra‐strand base‐pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, suggesting that (...) if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post‐replicative mechanism for the elimination and/orrepair of large DNA secondary structures. (shrink)

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The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excisionrepair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted multiple (...) pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overallrepair reaction. Our current understanding of DNA single-strand breakrepair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

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The bacterium Deinococcus (formerly Micrococcus) radiodurans and other members of the eubacterial family Deinococaceae are extremely resistant to ionizing radiation and many other agents that damage DNA. Stationary phase D. radiodurans exposed to 1.0‐1.5 Mrad γ‐irradiation sustains >120 DNA double‐strand breaks (dsbs) per chromosome; these dsbs are mended over a period of hours with 100% survival and virtually no mutagenesis. This contrasts with nearly all other organisms in which just a few ionizing radiation induced‐dsbs per chromosome are lethal. In this (...) article we present an hypothesis that resistance of D. radiodurans to ionizing radiation and its ability to mend radiation‐induced dsbs are due to a special form of redundancy wherein chromosomes exist in pairs, linked to each other by thousands of four‐stranded (Holliday) junctions. Thus, a dsb is not a lethal event because the identical undamaged duplex is nearby, providing an accuraterepair template. As addressed in this article, much of what is known about D. radiodurans suggests that it is particularly suited for this proposed novel form of DNArepair. (shrink)

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DNA mismatchrepair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatchrepair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6‐methylguanine and 6‐thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of (...) this defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatchrepair proteins that are causally related to these cancers. (shrink)

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Exocyclic DNA adducts are mutagenic lesions that can be formed by both exogenous and endogenous mutagens/carcinogens. These adducts are structurally analogs but can differ in certain features such as ring size, conjugation, planarity and substitution. Although the information on the biological role of therepair activities for these adducts is largely unknown, considerable progress has been made on their reaction mechanisms, substrate specificities and kinetic properties that are affected by adduct structures. At least four different mechanisms appear to have (...) evolved for the removal of specific exocyclic adducts. These include base excisionrepair, nucleotide excisionrepair, mismatchrepair, and AP endonuclease‐mediatedrepair. This overview highlights the recent progress in such areas with emphasis on structure–activity relationships. It is also apparent that more information is needed for a better understanding of the biological and structural implications of exocyclic adducts and theirrepair. BioEssays 26:1195–1208, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

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Two mechanisms are available for therepair of DNA double‐strand breaks (DSBs) in eukaryotic cells: homology directedrepair (HDR) and non‐homologous end‐joining (NHEJ). While NHEJ is not restricted to a particular phase of the cell cycle, it is incapable of accurately repairing DBSs that have suffered a loss or gain of nucleotide sequence information. In contrast, HDR achieves accuraterepair of such DSBs by use of a sister chromatid as a DNA template, but is restricted to cell (...) cycle phases (S/G2) when such templates are available. In this scheme, G1 cells appear to lack a mechanism for the accuraterepair of certain DSBs, and an ability to use alternative templates would be highly advantageous. Considered here, therefore, is the possibility that RNA transcripts are used as templates for HDR. Potential mechanisms for transcript‐templated HDR, and ways in which it might be detected, are presented. BioEssays 28:78–83, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

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DNA damagerepair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms torepair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNArepair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also (...) affect subtelomeric regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

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DNA double‐strand breaks (DSBs) are one of the most deleterious forms of DNA damage and can result in cell inviability or chromosomal aberrations. The Mre11‐Rad50‐Nbs1 (MRN) ATPase‐nuclease complex is a central player in the cellular response to DSBs and is implicated in the sensing and nucleolytic processing of DSBs, as well as in DSB signaling by activating the cell cycle checkpoint kinase ATM. ATP binding to Rad50 switches MRN from an open state with exposed Mre11 nuclease sites to a closed (...) state with partially buried nuclease sites. The functional meaning of this switch remained unclear. A new study shows that ATP binding to Rad50 promotes DSB recognition, tethering, and ATM activation, while ATP hydrolysis opens the nuclease active sites to promote processing of DSBs. MRN thus emerges as functional switch that may coordinate the temporal transition from signaling to processing of DSBs. (shrink)

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Replication protein A (RPA), the major single‐stranded DNA‐binding protein in eukaryotic cells, is required for processing of single‐stranded DNA (ssDNA) intermediates found in replication,repair, and recombination. Recent studies have shown that RPA binding to ssDNA is highly dynamic and that more than high‐affinity binding is needed for function. Analysis of DNA binding mutants identified forms of RPA with reduced affinity for ssDNA that are fully active, and other mutants with higher affinity that are inactive. Single molecule studies showed (...) that while RPA binds ssDNA with high affinity, the RPA complex can rapidly diffuse along ssDNA and be displaced by other proteins that act on ssDNA. Finally, dynamic DNA binding allows RPA to prevent error‐pronerepair of double‐stranded breaks and promote error‐freerepair. Together, these findings suggest a new paradigm where RPA acts as a first responder at sites with ssDNA, thereby actively coordinating DNArepair and DNA synthesis. (shrink)

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Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excisionrepair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNArepair mechanism, in processes that facilitate mRNA (...) synthesis or shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed. (shrink)

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RNA polymerase II is recruited to DNA double‐strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage‐induced long non‐coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA‐like molecules or degraded by different ribonucleases. They can also form double‐stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment ofrepair factors during the early steps of homologous recombination (HR) and, in this way, contribute (...) to the accuracy of the DNArepair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successfulrepair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR. (shrink)

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Unlike the most well‐characterized prokaryotic polymerase, E. Coli DNA pol I, none of the eukaryotic polymerases have their own 5′ to 3′ exonuclease domain for nick translation and Okazaki fragment processing. In eukaryotes, FEN‐1 is an endo‐and exonuclease that carries out this function independently of the polymerase molecules. Only seven nucleases have been cloned from multicellular eukaryotic cells. Among these, FEN‐1 is intriguing because it has complex structural preferences; specifically, it cleaves at branched DNA structures. The cloning of FEN‐1 permitted (...) establishment of the first eukaryotic nuclease family, predicting that S. cerevisiae RAD2 (S. pombe Rad13) and its mammalian homolog, XPG, would have similar structural specficity. The FEN‐1 nuclease family includes several similar enzymes encoded by bacteriophages. The crystal structures of two enzymes in the FEN‐1 nuclease family have been solved and they provide a structural basis for the interesting steric requirements of FEN‐1 substrates. Because of their unique structural specificities, FEN‐1 and its family members have important roles in DNA replication,repair and, potentially, recombination. Recently, FEN‐1 was found to specifically associate with PCNA, explaining some aspects of FEN‐1 function during DNA replication and potentially in DNArepair. (shrink)

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