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REV3 and REV1 play major roles in recombination-independent repair of DNA interstrand cross-links mediated by monoubiquitinated proliferating cell nuclear antigen (PCNA).

Journal article
Authors Xi Shen
Sohee Jun
Lindsey E O'Neal
Eiichiro Sonoda
Mats Bemark
Julian E Sale
Lei Li
Published in The Journal of biological chemistry
Volume 281
Issue 20
Pages 13869-72
ISSN 0021-9258
Publication year 2006
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 13869-72
Language en
Links dx.doi.org/10.1074/jbc.C600071200
Keywords Animals, Cell Line, Chickens, Cross-Linking Reagents, pharmacology, DNA Repair, DNA-Directed DNA Polymerase, physiology, Gene Deletion, Mice, Models, Genetic, Nucleotidyltransferases, physiology, Proliferating Cell Nuclear Antigen, chemistry, metabolism, Recombination, Genetic, Transgenes, Ubiquitin, chemistry
Subject categories Medical and Health Sciences

Abstract

DNA interstrand cross-links (ICLs) are the most cytotoxic lesions to eukaryotic genome and are repaired by both homologous recombination-dependent and -independent mechanisms. To better understand the role of lesion bypass polymerases in ICL repair, we investigated recombination-independent repair of ICLs in REV3 and REV1 deletion mutants constructed in avian DT40 cells and mouse embryonic fibroblast cells. Our results showed that Rev3 plays a major role in recombination-independent ICL repair, which may account for the extreme sensitivity of REV3 mutants to cross-linking agents. This result raised the possibility that the NER gap synthesis, when encountering an adducted base present in the ICL repair intermediate, can lead to recruitment of Rev3, analogous to the recruitment of polymerase eta during replicative synthesis. Indeed, the monoubiquitination-defective Proliferating Cell Nuclear Antigen (PCNA) mutant exhibits impaired recombination-independent ICL repair as well as drastically reduced mutation rate, indicating that the PCNA switch is utilized to enable lesion bypass during DNA repair synthesis. Analyses of a REV1 deletion mutant also revealed a significant reduction in recombination-independent ICL repair, suggesting that Rev1 cooperates with Rev3 in recombination-independent ICL repair. Moreover, deletion of REV3 or REV1 significantly altered the spectrum of mutations resulting from ICL repair, further confirming their involvement in mutagenic repair of ICLs.

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