Nibrin functions in Ig class-switch recombination

Abstract

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by predisposition to hematopoietic malignancy, cell-cycle checkpoint defects, and ionizing radiation sensitivity. NBS is caused by a hypomorphic mutation of the NBS1 gene, encoding nibrin, which forms a protein complex with Mre11 and Rad50, both involved in DNA repair. Nibrin localizes to chromosomal sites of class switching, and B cells from NBS patients show an enhanced presence of microhomologies at the sites of switch recombination. Because nibrin is crucial for embryonic survival, direct demonstration by targeted deletion that nibrin functions in class switch recombination has been lacking. Here, we show by cell-type-specific conditional inactivation of Nbn, the murine homologue of NBS1, that nibrin plays a role in the repair of ␥-irradiation damage, maintenance of chromosomal stability, and the recombination of Ig constant region genes in B lymphocytes.Nijmegen breakage syndrome ͉ B lymphocytes ͉ DNA repair

Liver X Receptors Control IgE Expression in B Cells

“…Proliferation of activated B cells was monitored on single-cell level by dilution of CFSE-fluorescence (Invitrogen) as described previously (22). Briefly, freshly isolated B cells were washed and resuspended in PBS at a final concentration of 10 7 cells/ml.…”

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

“…During SHM, both single-stranded DNA (ssDNA) breaks and DSB are scattered along the target V sequence. Very recently, the role of the MRE11/RAD50/NBS1 (MRN) complex has been demonstrated to be involved in the DSB sensing during CSR [Kracker et al, 2005;Lahdesmaki et al, 2004;Larson et al, 2005] and SHM [Yabuki et al, 2005].…”

Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair

“…Abasic sites are further processed to generate DNA double-strand breaks (DSBs), which are obligate intermediates in CSR (6, 7). The DSBs activate damage response proteins, such as PI3-like protein kinase ataxia-telangiectasia mutated, the phosphorylated histone variant H2AX, the MRN complex (MRE11, RAD50, and NBS1), MDC1, and 53BP1, all of which are known to play roles in CSR in promoting appropriate repair and efficient long-range, region-specific recombination (8)(9)(10)(11)(12)(13)(14). In CSR, the resolution step is normally mediated by the classical nonhomologous end-joining pathway (c-NHEJ); however, recent reports strongly suggest that resolution also can be mediated (albeit at a lower frequency) by Ku 70-, Ku 80-, and/or XRCC4/DNA ligase 4-independent alternative end-joining (AEJ) pathways, which are biased toward microhomology usage, and which components are not yet well defined (15-18).…”