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Activation-Induced Cytidine Deaminase-Dependent DNA Breaks in Class Switch Recombination Occur during G₁ Phase of the Cell Cycle and Depend upon Mismatch Repair¹

Carol E. Schrader^2,*, Jeroen E. J. Guikema^*, Erin K. Linehan^*, Erik Selsing and Janet Stavnezer^2,*

^* Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655; and Genetics Program and the Department of Pathology, Tufts University School of Medicine, Boston, MA 02111

Ab class switching occurs by an intrachromosomal recombination and requires generation of double-strand breaks (DSBs) in Ig switch (S) regions. Activation-induced cytidine deaminase (AID) converts cytosines in S regions to uracils, which are excised by uracil DNA glycosylase (UNG). Repair of the resulting abasic sites would yield single-strand breaks (SSBs), but how these SSBs are converted to DSBs is unclear. In mouse splenic B cells, we find that AID-dependent DSBs occur in Sµ mainly in the G₁ phase of the cell cycle, indicating they are not created by replication across SSBs. Also, G₁ phase cells express AID, UNG, and mismatch repair (MMR) proteins and possess UNG activity. We find fewer S region DSBs in MMR-deficient B cells than in wild-type B cells, and still fewer in MMR-deficient/SµTR^–/– B cells, where targets for AID are sparse. These DSBs occur predominantly at AID targets. We also show that nucleotide excision repair does not contribute to class switching. Our data support the hypothesis that MMR is required to convert SSBs into DSBs when SSBs on opposite strands are too distal to form DSBs spontaneously.

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 This work was supported by National Institutes of Health Grants AI065639 (to C.E.S.), AI23283 and AI632026 (to J.S.), and by the Cancer Research Institute (to J.E.J.G.).

² Address correspondence and reprint requests to Dr. Carol E. Schrader and Dr Janet Stavnezer, Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655; E-mail addresses: Carol.Schrader{at}umassmed.edu or Janet.Stavnezer{at}umassmed.edu

³ Abbreviations used in this paper: CSR, class switch recombination; DSB, double-strand break; AID, activation-induced cytidine deaminase; TR, tandem repeat; UNG, uracil DNA glycosylase; APE, AP endonuclease; SSB, single-strand break; NER, nucleotide excision repair; MMR, mismatch repair; WT, wild type; LM-PCR, ligation-mediated PCR; XPF, Xeroderma pigmentosum F.

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				J. E.J. Guikema, E. K. Linehan, D. Tsuchimoto, Y. Nakabeppu, P. R. Strauss, J. Stavnezer, and C. E. Schrader APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination J. Exp. Med., November 26, 2007; 204(12): 3017 - 3026. [Abstract] [Full Text] [PDF]