title: XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes.
abstract: Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer's patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1(+/-) splenic B cells, the length of microhomology at the switch junctions decreased, suggesting that XRCC1 also participates in alternative nonhomologous end joining. Furthermore, Xrcc1(+/-) B cells had reduced Igh/c-myc translocations during CSR, supporting a role for XRCC1 in microhomology-mediated joining. Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways.
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA..
authors.forename: Huseyin
authors.initials: H
authors.lastname: Saribasak
authors.forename: Robert W
authors.initials: RW
authors.lastname: Maul
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: McClure
authors.forename: William
authors.initials: W
authors.lastname: Yang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McNeill
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005803:Genes, Immunoglobulin; D017578:Immunoglobulin Class Switching; D007134:Immunoglobulin Switch Region; D051379:Mice; D008810:Mice, Inbred C57BL; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619352:Xrcc1 protein, mouse; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase