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* Department of Molecular Genetic and Cell Biology,
Committee on Immunology, and
Department of Statistics, University of Chicago, Chicago, IL 60637
Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytosine deaminase (AID). The uracil, and potentially neighboring bases, are processed by error-prone base excision repair and mismatch repair. Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR. To determine whether Msh2/Msh6 complexes which recognize single-base mismatches and loops were the only mismatch-recognition complexes required for SHM and CSR, we analyzed these processes in Msh6–/–Ung–/– mice. SHM and CSR were affected in the same degree and fashion as in Msh2–/–Ung–/– mice; mutations were mostly C,G transitions and CSR was greatly reduced, making Msh2/Msh3 contributions unlikely. Inactivating Ung alone reduced mutations from A and T, suggesting that, depending on the DNA sequence, varying proportions of A,T mutations arise by error-prone long-patch base excision repair. Further, in Msh6–/–Ung–/– mice the 5' end and the 3' region of Ig genes was spared from mutations as in wild-type mice, confirming that AID does not act in these regions. Finally, because in the absence of both Ung and Msh6, transition mutations from C and G likely are "footprints" of AID, the data show that the activity of AID is restricted drastically in vivo compared with AID in cell-free assays.
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1 This work was supported by National Institutes of Health Grants AI47380 and AI053130.
2 Address correspondence and reprint requests to Dr. Ursula Storb, Department of Molecular Genetics and Cell Biology, University of Chicago, 920 East 58th Street, Chicago, IL 60637. E-mail address: stor{at}midway.uchicago.edu
3 Abbreviations used in this paper: AID, activation-induced cytosine deaminase; SHM, somatic hypermutation; CSR, class switch recombination; BER, base excision repair; MMR, mismatch repair; SRBC, sheep RBC; PNA, peanut lectin agglutinin.
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