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A Critical Role for REV1 in Regulating the Induction of C:G Transitions and A:T Mutations during Ig Gene Hypermutation

Keiji Masuda^*, Rika Ouchida^*, Yingqian Li^,*, Xiang Gao, Hiromi Mori^* and Ji-Yang Wang^1,*

^* Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan; and Model Animal Research Center, Ministry of Education Key Laboratory of Model Animal for Disease Research, Medical School of Nanjing University, Nanjing, China

REV1 is a deoxycytidyl transferase that catalyzes the incorporation of deoxycytidines opposite deoxyguanines and abasic sites. To explore the role of its catalytic activity in Ig gene hypermutation in mammalian cells, we have generated mice expressing a catalytically inactive REV1 (REV1AA). REV1AA mice developed normally and were fertile on a pure C57BL/6 genetic background. B and T cell development and maturation were not affected, and REV1AA B cells underwent normal activation and class switch recombination. Analysis of Ig gene hypermutation in REV1AA mice revealed a great decrease of C to G and G to C transversions, consistent with the disruption of its deoxycytidyl transferase activity. Intriguingly, REV1AA mice also exhibited a significant reduction of C to T and G to A transitions. Moreover, each type of nucleotide substitutions at A:T base pairs was uniformly reduced in REV1AA mice, a phenotype similar to that observed in mice haploinsufficient for Polh. These results reveal an unexpected role for REV1 in the generation of C:G transitions and A:T mutations and suggest that REV1 is involved in multiple mutagenic pathways through functional interaction with other polymerases during the hypermutation process.

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.

¹ Address correspondence and reprint requests to Dr. Ji-Yang Wang, Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan. E-mail address: oh{at}rcai.riken.jp

² Abbreviations used in this paper: SHM, somatic hypermutation; BRCT, BRCA1 C-terminal; GC, germinal center; MMS, methyl methanesulfonate; POLH, polymerase ; REV1AA, catalytically inactive REV1; UNG, uracil DNA glycosylase; WT, wild type.

³ The online version of this article contains supplemental material.

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The JI 2009 183: 1501-1502. [Full Text]