Multiple roles of Rev3, the catalytic subunit of pol  in maintaining genome stability in vertebrates

Sonoda, Eiichiro; Okada, Takashi; Zhao, Guang Yu; Tateishi, Seiichiro; Araki, Koji; Yamaizumi, Masaru; Yagi, Takashi; Verkaik, Nicole S.; Gent, Dik C. van; Takata, Minoru; Takeda, Shunichi

doi:10.1093/emboj/cdg308

Cited by 186 publications

(209 citation statements)

References 76 publications

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“…In particular, they have also been implicated in the regulation of translesion polymerases in postreplication repair (16,17), but the function of these polymerases in other genetic processes in eukaryotes may also be regulated by different means, i.e., independently of the Rad6 pathway (18)(19)(20). In the present study, we show that the crucial initiator factor of the Rad6 pathway, Rad18, plays a role during somatic hypermutation in the DT40 B cell line.…”

mentioning

confidence: 48%

Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

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

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Somatic hypermutation of Ig genes is initiated by transcriptioncoupled cytidine deamination in Ig loci. Error-prone processing of the resultant DNA lesions is thought to cause extensive mutagenesis, but it is presently an enigma how and why error-prone rather than error-free repair pathways are recruited. During DNA replication, recruitment of error-prone translesion polymerases may be mediated by Rad6͞Rad18-mediated ubiquitination of proliferating cell nuclear antigen, a major switchboard controlling the fidelity of DNA lesion bypass in eukaryotes. By inactivation of Rad18 in the DT40 B cell line, we show that the Rad6 pathway is involved in somatic hypermutation in these cells. Our findings imply that targeted recruitment of mutagenic polymerases by the Rad6 pathway contributes to the complex process of somatic hypermutation and provide a framework for more detailed mechanistic studies of the mutagenesis phase of secondary Ig diversification.proliferating cell nuclear antigen ͉ ubiquitination ͉ Rad6 pathway G iven the many challenges that damage cellular DNA daily, the faithful maintenance of genetic information requires the interplay of multiple DNA repair pathways. In most cases, these mechanisms ensure restoration of the original DNA sequence, preventing mutations or aberrations that may lead to impairment of cellular function. In some instances, though, a certain imprecision may be tolerated or even favored by the cell to allow for survival in critical situations. DNA repair mechanisms that are inherently imprecise are the basis of the spontaneous mutability of all genomes and may be recruited and adapted for situations where high genetic variability is mandatory for survival.The adaptive immune system of vertebrates has been shaped in coevolution with pathogenic organisms of high genetic diversity and variability. The high diversity of the primary immune repertoire established during V(D)J recombination in B and T cells generates sufficient potential for recognition of any pathogen, but the affinity of binding is often not sufficient for effective neutralization. Therefore, a second wave of diversification during acute infections ensures that the binding affinity of the antibodies produced by B lymphocytes is fine-tuned to the task at hand. The underlying mechanism in humans is somatic hypermutation, which modifies the antigen binding region by targeted mutagenesis in the variable region of the Ig genes (1). An alternative diversification mechanism prevalent in chicken and some mammals, Ig gene conversion alters the same region by targeted homologous recombination with upstream Ig pseudogenes (2).Somatic hypermutation and Ig gene conversion are related processes (3) originating from the same initial DNA lesion. The transcription-coupled deamination of cytosines by activationinduced cytidine deaminase (AID) leads to uracil that may be processed to abasic sites or strand breaks by the excision repair pathway, i.e., uracil-N-glycosylase (4, 5). The resultant DNA lesions may be repaired by mutagenesis or reco...

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mentioning

confidence: 48%

Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

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

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“…Further, overexpression of REV1 in ovarian tumor lines led to some resistance to cisplatin and increased mutagenic frequency compared to parental lines [64]. Among DNA repair gene knockouts in chicken DT40 cells, rev3 mutants are the most sensitive to cisplatin of any single mutant examined [65]. Vertebrate REV3 and REV1 apparently play a more important role in cellular tolerance of some DNA-damaging agents than others.…”

Section: Consequences Of Rev3l Rev1 and Rev7 Reduction In Human Cellmentioning

confidence: 98%

“…Single disruption mutants of these genes were reported to have increased frequencies of sister chromatid exchange, both spontaneously and in response to 4-nitroquinolone-1-oxide and UV radiation [65,66]. An independent study using the same REV3L-disrupted cell line found that sister chromatid exchanges were still induced normally by 4-nitroquinolone-1-oxide, but were not induced by treatment with mitomycin C or cisplatin [67].…”

Section: Role Of Pol ζ In Interstrand Crosslink Repair and Recombinationmentioning

confidence: 99%

DNA polymerase zeta (pol ζ) in higher eukaryotes

et al. 2007

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Most current knowledge about DNA polymerase zeta (pol ζ) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol ζ can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7(MAD2B) in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

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“…To assess the role of SLX4 in HR-dependent double-strand break (DSB) repair, we exposed the SLX4 −/− tetSLX4 cells to γ rays (2 Gy) at 48 h after the addition of doxycycline, harvested mitotic cells 3 h later, and counted the number of chromosomal breaks. Using this protocol, we were able to selectively evaluate HRdependent DSB repair in the G 2 phase, because only cells irradiated in G 2 and not in S enter mitosis within 3 h, and also because cells in the G 2 phase preferentially use HR for DSB repair (31,32). In WT cells, ionizing radiation induced predominantly chromatid-type breaks (i.e., breaks in one sister chromatid).…”

Section: Slx4 Is Essential For Cell Proliferationmentioning

confidence: 99%

Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway

Yamamoto

Kobayashi

Tsuda

et al. 2011

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

178

156

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Interstrand cross-links (ICLs) block replication and transcription and thus are highly cytotoxic. In higher eukaryotes, ICLs processing involves the Fanconi anemia (FA) pathway and homologous recombination. Stalled replication forks activate the eight-subunit FA core complex, which ubiquitylates FANCD2-FANCI. Once it is posttranslationally modified, this heterodimer recruits downstream members of the ICL repairosome, including the FAN1 nuclease. However, ICL processing has been shown to also involve MUS81-EME1 and XPF-ERCC1, nucleases known to interact with SLX4, a docking protein that also can bind another nuclease, SLX1. To investigate the role of SLX4 more closely, we disrupted the SLX4 gene in avian DT40 cells. SLX4 deficiency caused cell death associated with extensive chromosomal aberrations, including a significant fraction of isochromatid-type breaks, with sister chromatids broken at the same site. SLX4 thus appears to play an essential role in cell proliferation, probably by promoting the resolution of interchromatid homologous recombination intermediates. Because ubiquitylation plays a key role in the FA pathway, and because the N-terminal region of SLX4 contains a ubiquitinbinding zinc finger (UBZ) domain, we asked whether this domain is required for ICL processing. We found that SLX4 −/− cells expressing UBZ-deficient SLX4 were selectively sensitive to ICL-inducing agents, and that the UBZ domain was required for interaction of SLX4 with ubiquitylated FANCD2 and for its recruitment to DNAdamage foci generated by ICL-inducing agents. Our findings thus suggest that ubiquitylated FANCD2 recruits SLX4 to DNA damage sites, where it mediates the resolution of recombination intermediates generated during the processing of ICLs.endonuclease | mitomycin C | cisplatin | DNA repair I nterstrand cross-links (ICLs) inhibit transcription and replication. Their considerable cytotoxicity has been ascribed primarily to their blockage of replication forks, and this phenomenon is believed to be responsible for the success of ICL-inducing agents, such as cisplatin and mitomycin-C (MMC), in cancer chemotherapy (1). ICL processing is complex, involving proteins from several distinct pathways of DNA metabolism. In higher organisms, ICL processing is orchestrated by the Fanconi anemia (FA) pathway (2, 3). Collision of replication forks with ICLs activates the ATR kinase, which in turn licenses the FANCL ubiquitin ligase subunit of the FA core complex (composed of FANCA, B, C, E, F, G, L and M proteins) to modify the FANCD2-FANCI heterodimer (2, 4-6). The monoubiquitylated FANCD2-FANCI complex is then targeted to chromatin (7,8), where it recruits downstream components of the repairosome, including the structure-specific nuclease FAN1 (9-12). However, ICL processing also requires other enzymes, such as the nucleases MUS81-EME1 and XPF-ERCC1, and how these are recruited to sites of damage in ICL repair is not known.The structure-specific endonucleases XPF-ERCC1 and MUS81-EME1, which are implicated in ICL repair and in the res...

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Multiple roles of Rev3, the catalytic subunit of pol in maintaining genome stability in vertebrates

Cited by 186 publications

References 76 publications

Involvement of Rad18 in somatic hypermutation

Involvement of Rad18 in somatic hypermutation

DNA polymerase zeta (pol ζ) in higher eukaryotes

Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway

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