Article
- The EMBO Journal (2005) 24, 3757 - 3769
- doi:10.1038/sj.emboj.7600833
Published online: 13 October 2005
Subject Categories:
The translesion DNA polymerase 
plays a dominant role in immunoglobulin gene somatic hypermutation
Hong Zan1, Naoko Shima2, Zhenming Xu1, Ahmed Al-Qahtani1, Albert J Evinger III1, Yuan Zhong1, John C Schimenti2 and Paolo Casali1
- Center for Immunology, School of Medicine and School of Biological Sciences, University of California, Irvine, CA, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Correspondence to:
Paolo Casali, Center for Immunology, 3028 Hewitt Hall, University of California, Irvine, CA 92697-4120, USA. Tel.: +1 949 824 4456; Fax: +1 949 824 2305; E-mail: pcasali@uci.edu
Received 7 July 2005; Accepted 12 September 2005
Abstract
Immunoglobulin (Ig) somatic hypermutation (SHM) critically underlies the generation of high-affinity antibodies. Mutations can be introduced by error-prone polymerases such as polymerase 
(Rev3), a mispair extender, and polymerase 
, a mispair inserter with a preference for dA/dT, while repairing DNA lesions initiated by AID-mediated deamination of dC to yield dU:dG mismatches. The partial impairment of SHM observed in the absence of these polymerases led us to hypothesize a main role for another translesion DNA polymerase. Here, we show that deletion in C57BL/6J mice of the translesion polymerase 
, which possesses a dual nucleotide mispair inserter–extender function, results in greater than 60% decrease of mutations in antigen-selected V186.2DJH transcripts and greater than 80% decrease in mutations in the Ig H chain intronic JH4-iE
sequence, together with significant alterations in the spectrum of the residual mutations. Thus, polymerase plays a dominant role in SHM, possibly by introducing mismatches while bypassing abasic sites generated by UDG-mediated deglycosylation of AID-effected dU, by extending DNA past such abasic sites and by synthesizing DNA during dU:dG mismatch repair.
Keywords:
- antibody,
- DNA polymerase ,
- DNA repair,
- somatic hypermutation,
- translesion DNA polymerase
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