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Originally published In Press as doi:10.1074/jbc.C600071200 on March 29, 2006
J. Biol. Chem., Vol. 281, Issue 20, 13869-13872, May 19, 2006
REV3 and REV1 Play Major Roles in Recombination-independent Repair of DNA Interstrand Cross-links Mediated by Monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA)*
Xi Shen ,
Sohee Jun ,
Lindsey E. O'Neal ,
Eiichiro Sonoda ,
Mats Bemark¶,
Julian E. Sale||, and
Lei Li **1
From the
Department of Experimental Radiation Oncology and **Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan, the ¶University of Goteborg, Guldhedsgatan 10, SE413 46 Goteborg, Sweden, and the ||Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom
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 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.
Received for publication, March 22, 2006
, and in revised form, March 29, 2006.
* This work was supported by NCI/National Institutes of Health Grants CA97175 (to L. L.), CA91029 (to L. L.), the United Kingdom Medical Research Council (to J. E. S), the Leukemia Research Fund and Association for International Cancer Research (to J. E. S.), the Swedish Cancer Society (to M. B.), and the Swedish Research Council (to M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.
1 To whom correspondence should be addressed. Tel.: 713-792-2514; Fax: 713-794-5369; E-mail: leili{at}mdanderson.org.

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