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Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655

CORRESPONDENCE Janet Stavnezer: Janet.Stavnezer{at}umassmed.edu

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), which converts cytosines to uracils in switch (S) regions. Subsequent excision of dU by uracil DNA glycosylase (UNG) of the base excision repair (BER) pathway is required to obtain double-strand break (DSB) intermediates for CSR. Since UNG normally initiates faithful repair, it is unclear how the AID-instigated S region lesions are converted into DSBs rather than correctly repaired by BER. Normally, DNA polymerase ß (Polß) would replace the dC deaminated by AID, leading to correct repair of the single-strand break, thereby preventing CSR. We address the question of whether Polß might be specifically down-regulated during CSR or inhibited from accessing the AID-instigated lesions, or whether the numerous AID-initiated S region lesions might simply overwhelm the BER capacity. We find that nuclear Polß levels are induced upon activation of splenic B cells to undergo CSR. When Polß^–/– B cells are activated to switch in culture, they switch slightly better to IgG2a, IgG2b, and IgG3 and have more S region DSBs and mutations than wild-type controls. We conclude that Polß attempts to faithfully repair S region lesions but fails to repair them all.

Abbreviations used: --dex, anti-IgD conjugated to dextran; AID, activation-induced cytidine deaminase; APE, apurinic/apyrimidic endonuclease; BER, base excision repair; C, constant region of IgA heavy chain; ChIP, chromatin immunoprecipitation; CSR, class switch recombination; dRP, 5'-deoxyribose phosphate; DSB, double-strand break; FI, fluorescence intensity; FLC, fetal liver cell; GL, germline; LM-PCR, ligation-mediated PCR; MEF, mouse embryonic fibroblast; MMR, mismatch repair; Polß, DNA polymerase ß; S, switch; SHM, somatic hypermutation; Sµ, µ gene S region; SMUG, single-strand selective monofunctional uracil glycosylase; SSB, single-strand break; UNG, uracil DNA glycosylase.

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This article has been cited by other articles:

• Guikema, J. E.J., Linehan, E. K., Tsuchimoto, D., Nakabeppu, Y., Strauss, P. R., Stavnezer, J., Schrader, C. E. (2007). APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. J. Exp. Med. 204: 3017-3026 [Abstract] [Full Text]  

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