RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells

Yamashita, Yukiko; Okada, Takashi; Matsusaka, Takahiro; Sonoda, Eiichiro; Zhao, Guang Yu; Araki, Koji; Tateishi, Seiichiro; Yamaizumi, Masaru; Takeda, Shunichi

doi:10.1093/emboj/cdf534

Cited by 125 publications

(132 citation statements)

References 41 publications

(55 reference statements)

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“…As shown before, Rad18 deficiency did not adversely affect cell viability or proliferation (15,22). Treatment with methylmethanesulfonate resulted in efficient PCNA monoubiqitination in WT cells (Fig.…”

Section: Resultssupporting

confidence: 74%

“…The relative activity of hypermutation may be enhanced by impairment of homologous recombination in cis [i.e., by deletion of the pseudogene locus (3)] or in trans [e.g., by inactivation of XRCC2͞3 (24)]. The latter approach is not suitable in the present context, as combined inactivation of homologous recombination and the Rad6 pathway is synthetic lethal in DT40 (15).…”

Section: Resultsmentioning

confidence: 99%

“…The DT40 system, as most other in vitro hypermutation models, does not allow substantial analyses of A͞T mutagenesis (3). Concerning G͞C-biased mutagenesis, Rad18 might function specifically during translesion synthesis over abasic sites, which is required for G͞C transversions but may also insert transitions (15,27), and͞or might be involved in the recruitment of mismatch extenders such as Pol and Pol that appear to affect the overall mutation load rather than specific subpathways (9,(32)(33)(34). Clearly, all types of mutations are negatively affected by Rad18 deficiency (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Components of the Rad6 pathway are conserved in higher eukaryotes and have been implicated in the regulation of mutagenic and recombinogenic DNA modifications (14,15). 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).…”

mentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

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

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“…In contrast, RAD5 and RAD6 deletions did not affect the DSBinduced conversion pattern. RAD18 deficiency in chicken lymphocytes has been reported to decrease targeted integrations (49), indicating that this PRR gene affects some forms of homologous recombination.…”

Section: Discussionmentioning

confidence: 99%

DNA Repair Defects Channel Interstrand DNA Cross-links into Alternate Recombinational and Error-prone Repair Pathways

Saffran

Ahmed

Bellevue

et al. 2004

Journal of Biological Chemistry

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The repair of psoralen interstrand cross-links in the yeast Saccharomyces cerevisiae involves the DNA repair groups nucleotide excision repair (NER), homologous recombination (HR), and post-replication repair (PRR). In repair-proficient yeast cells cross-links induce double-strand breaks, in an NER-dependent process; the double-strand breaks are then repaired by HR. An alternate error-prone repair pathway generates mutations at cross-link sites. We have characterized the repair of plasmid molecules carrying a single psoralen cross-link, psoralen monoadduct, or double-strand break in yeast cells with deficiencies in NER, HR, or PRR genes, measuring the repair efficiencies and the levels of gene conversions, crossing over, and mutations. Strains with deficiencies in the NER genes RAD1, RAD3, RAD4, and RAD10 had low levels of cross-link-induced recombination but higher mutation frequencies than repair-proficient cells. Deletion of the HR genes RAD51, RAD52, RAD54, RAD55, and RAD57 also decreased induced recombination and increased mutation frequencies above those of NER-deficient yeast. Strains lacking the PRR genes RAD5, RAD6, and RAD18 did not have any crosslink-induced mutations but showed increased levels of recombination; rad5 and rad6 cells also had altered patterns of cross-link-induced gene conversion in comparison with repair-proficient yeast. Our observations suggest that psoralen cross-links can be repaired by three pathways: an error-free recombinational pathway requiring NER and HR and two PRR-dependent errorprone pathways, one NER-dependent and one NERindependent.DNA interstrand cross-links are complex lesions, highly toxic to cells, and difficult to repair because of the involvement of both strands of the DNA duplex. A single unrepaired interstrand cross-link is sufficient to kill a cell, and multiple DNA repair pathways may be required to complete cross-link removal (1-7).The yeast Saccharomyces cerevisiae has three major DNA repair epistasis groups, all of which are involved in cross-link repair; they are nucleotide excision repair, recombinational repair, and post-replication repair (8). Nucleotide excision repair (NER) 1 is a general system that recognizes bulky and helix-distorting lesions (9, 10). Endonucleases nick the affected DNA strand on both the 5Ј and 3Ј sides of the lesion; after removal of the damaged oligonucleotide, the resulting singlestrand gap is filled in by polymerase activity using the undamaged strand as a template. This mechanism produces error-free repair of single-strand damage. Recombinational repair is the major pathway for repair of double-strand damage, such as double-strand breaks (DSBs) or gaps in yeast (11,12). In homologous recombination (HR) the broken DNA molecule is repaired, and missing genetic information is restored through interactions with intact homologous sequences. This pathway is also non-mutagenic but can result in DNA rearrangements. Post-replication repair (PRR) acts on damage in the context of DNA replication, allowing for bypass of replication fork-...

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Recombination and Genome Rearrangements

Klein

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells

Cited by 125 publications

References 41 publications

Involvement of Rad18 in somatic hypermutation

Involvement of Rad18 in somatic hypermutation

DNA Repair Defects Channel Interstrand DNA Cross-links into Alternate Recombinational and Error-prone Repair Pathways

Recombination and Genome Rearrangements

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