Three DNA Polymerases, Recruited by Different Mechanisms, Carry Out NER Repair Synthesis in Human Cells

Ogi, Tomoo; Limsirichaikul, Siripan; Overmeer, René M.; Volker, Marcel; Takenaka, Kazumasa; Cloney, Ross; Nakazawa, Yuka; Niimi, Atsuko; Miki, Yoshio; Jaspers, Nicolaas G. J.; Mullenders, Leon H.F.; Yamashita, Shunichi; Fousteri, Maria; Lehmann, Alan R.

doi:10.1016/j.molcel.2010.02.009

Cited by 341 publications

(300 citation statements)

References 54 publications

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“…8). Consistent with this result, the error-prone Y family DNA polymerase Pol κ has been shown to have an important role in NER for repair synthesis in mammalian cells (40,41). Apart from its other functions, this polymerase might be used to deal with closely opposed DNA lesions.…”

Section: Compromised Tls Activity Leads To Increased Recombinant Molementioning

confidence: 66%

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Westmoreland

Resnick

2013

Proc. Natl. Acad. Sci. U.S.A.

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Repair of DNA bulky lesions often involves multiple repair pathways such as nucleotide-excision repair, translesion DNA synthesis (TLS), and homologous recombination (HR). Although there is considerable information about individual pathways, little is known about the complex interactions or extent to which damage in single strands, such as the damage generated by UV, can result in double-strand breaks (DSBs) and/or generate HR. We investigated the consequences of UV-induced lesions in nonreplicating G2 cells of budding yeast. In contrast to WT cells, there was a dramatic increase in ssDNA gaps for cells deficient in the TLS polymerases η (Rad30) and ζ (Rev3). Surprisingly, repair in TLS-deficient G2 cells required HR repair genes RAD51 and RAD52, directly revealing a redundancy of TLS and HR functions in repair of ssDNAs. Using a physical assay that detects recombination between circular sister chromatids within a few hours after UV, we show an approximate three-fold increase in recombinants in the TLS mutants over that in WT cells. The recombination, which required RAD51 and RAD52, does not appear to be caused by DSBs, because a dose of ionizing radiation producing 20 times more DSBs was much less efficient than UV in producing recombinants. Thus, in addition to revealing TLS and HR functional redundancy, we establish that UV-induced recombination in TLS mutants is not attributable to DSBs. These findings suggest that ssDNA that might originate during the repair of closely opposed lesions or of ssDNA-containing lesions or from uncoupled replication may drive recombination directly in various species, including humans.

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Section: Compromised Tls Activity Leads To Increased Recombinant Molementioning

confidence: 66%

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Westmoreland

Resnick

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In a mammalian cell, this process occurs 20 -50 million times during every cell cycle (23). Pol ␦ also participates in DNA repair as a gap-filling polymerase, including nucleotide excision repair, mismatch repair, and base excision repair (70,(83)(84)(85)(86)(87)(88). ATR and ATR orthologues in yeast may stabilize replication forks that have stalled as the result of DNA polymerase inhibition (13)(14)(15)17).…”

Section: Discussionmentioning

confidence: 99%

Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Huang

Fang

et al. 2011

Journal of Biological Chemistry

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Perturbation of cell cycle regulation is a characteristic feature of infection by many DNA and RNA viruses, including Coronavirus infectious bronchitis virus (IBV). IBV infection was shown to induce cell cycle arrest at both S and G 2 /M phases for the enhancement of viral replication and progeny production. However, the underlying mechanisms are not well explored. In this study we show that activation of cellular DNA damage response is one of the mechanisms exploited by Coronavirus to induce cell cycle arrest. An ATR-dependent cellular DNA damage response was shown to be activated by IBV infection. Suppression of the ATR kinase activity by chemical inhibitors and siRNA-mediated knockdown of ATR reduced the IBV-induced ATR signaling and inhibited the replication of IBV. Furthermore, yeast two-hybrid screens and subsequent biochemical and functional studies demonstrated that interaction between Coronavirus nsp13 and DNA polymerase ␦ induced DNA replication stress in IBV-infected cells. These findings indicate that the ATR signaling activated by IBV replication contributes to the IBV-induced S-phase arrest and is required for efficient IBV replication and progeny production.DNA damage response is a signal transduction pathway that coordinates cell cycle transition, DNA replication, and repair in response to DNA damage or replication stress (1, 2). It is essential for maintenance of genome integrity and cell survival. DNA damage response is primarily mediated by two related protein kinases, the ataxia-telangiectasia mutated (ATM) 2 and ATM/ Rad3-related (ATR). ATM is activated as a result of doublestranded breaks (DSBs) and is recruited to DSBs by Mre11-Rad50-NBS1 complex (3, 4). ATR, on the other hand, is activated by a wide range of DNA damage, including stalled DNA replication forks and the subsequent single-stranded lesion (ssDNA), base adducts, ultraviolet (UV)-induced nucleotide damage, and double-stranded breaks during S phase (1, 5). ATR is recruited to replication factor A (RPA)-coated ssDNA by ATR-interacting protein (ATRIP) (6, 7). When ATM or ATR is recruited to sites of damage, they phosphorylate and activate different substrates, including checkpoint kinase-2 (CHK2) and CHK1, respectively (1,8,9). A large number of overlapping substrates of ATM and ATR that might be involved in DNA damage response has been presented (e.g. H2AX, RPA32, p53, BRCA1) (10, 11). Those signaling modules finally lead to cell cycle arrest to allow for DNA repair or apoptosis in cases of severe DNA damage. In contrast to ATM, ATR prevents replication fork collapse at stalled replication forks and is essential for cell viability (7,(12)(13)(14)(15)(16)(17)(18).Many DNA viruses and retroviruses, including Epstein-Barr virus, herpes simplex virus 1, human Papillomavirus 16, human immunodeficiency virus (HIV), adenovirus, simian virus 40 (SV40), and Polyomavirus, are known to eliminate, circumvent, or exploit various aspects of cellular DNA damage response machinery to maximize their own replication. In RNA virus families, however,...

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“…The mechanism involves the generation of ssDNA and its coating by RPA as an essential step of nucleotide excision repair (NER), which leads to the recruitment of ATR and ATRinteracting protein (ATRIP) [Matsumoto et al, 2007;Vrouwe et al, 2011]. Because UV-induced damage lesions are repaired by NER, this could provide the source of ATR activation that is required for p12 degradation and is also consistent with the known recruitment of Pol d to NER repair sites [Mocquet et al, 2008;Ogi et al, 2010].…”

Section: Degradation Of P12 and The Conversion Of Pol D4 To Pol D3 Inmentioning

confidence: 90%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

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Three DNA Polymerases, Recruited by Different Mechanisms, Carry Out NER Repair Synthesis in Human Cells

Cited by 341 publications

References 54 publications

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

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