Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining. Export

@article{citeulike:2752841, abstract = {The tumor suppressor gene BRCA1 maintains genomic integrity by protecting cells from the deleterious effects of DNA double-strand breaks (DSBs). Through its interactions with the checkpoint kinase 2 (Chk2) kinase and Rad51, BRCA1 promotes homologous recombination, which is typically an error-free repair process. In addition, accumulating evidence implicates BRCA1 in the regulation of nonhomologous end-joining (NHEJ), which may involve precise religation of the DSB ends if they are compatible (i.e., error-free repair) or sequence alteration upon rejoining (i.e., error-prone or mutagenic repair). However, the precise role of BRCA1 in regulating these different subtypes of NHEJ is not clear. We provide here the genetic and biochemical evidence to show that BRCA1 promotes error-free rejoining of DSBs in human breast carcinoma cells while suppressing microhomology-mediated error-prone end-joining and restricting sequence deletion at the break junction during repair. The repair spectrum in BRCA1-deficient cells was characterized by an increase in the formation of >2 kb deletions and in the usage of long microhomologies distal to the break site, compared with wild-type (WT) cells. This error-prone repair phenotype could also be revealed by disruption of the Chk2 phosphorylation site of BRCA1, or by expression of a dominant-negative kinase-dead Chk2 mutant in cells with WT BRCA1. We suggest that the differential control of NHEJ subprocesses by BRCA1, in concert with Chk2, reduces the mutagenic potential of NHEJ, thereby contributing to the prevention of familial breast cancers.}, address = {Department of Radiation Oncology, Vanderbilt University Medical Centre, 1301 22nd Avenue South, Nashville, TN 37232, USA.}, author = {Zhuang, J. and Zhang, J. and Willers, H. and Wang, H. and Chung, J. H. and van Gent, D. C. and Hallahan, D. E. and Powell, S. N. and Xia, F.}, citeulike-article-id = {2752841}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/0008-5472.CAN-05-3278}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16452195}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16452195}, day = {1}, doi = {10.1158/0008-5472.CAN-05-3278}, issn = {0008-5472}, journal = {Cancer research}, keywords = {brca1, damage, dna, dsb, hr, nhej, repair}, month = {February}, number = {3}, pages = {1401--1408}, posted-at = {2008-05-04 05:45:24}, priority = {4}, title = {Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining.}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-05-3278}, volume = {66}, year = {2006} }

TY - JOUR ID - citeulike:2752841 L3 - citeulike-article-id:2752841 N2 - The tumor suppressor gene BRCA1 maintains genomic integrity by protecting cells from the deleterious effects of DNA double-strand breaks (DSBs). Through its interactions with the checkpoint kinase 2 (Chk2) kinase and Rad51, BRCA1 promotes homologous recombination, which is typically an error-free repair process. In addition, accumulating evidence implicates BRCA1 in the regulation of nonhomologous end-joining (NHEJ), which may involve precise religation of the DSB ends if they are compatible (i.e., error-free repair) or sequence alteration upon rejoining (i.e., error-prone or mutagenic repair). However, the precise role of BRCA1 in regulating these different subtypes of NHEJ is not clear. We provide here the genetic and biochemical evidence to show that BRCA1 promotes error-free rejoining of DSBs in human breast carcinoma cells while suppressing microhomology-mediated error-prone end-joining and restricting sequence deletion at the break junction during repair. The repair spectrum in BRCA1-deficient cells was characterized by an increase in the formation of >2 kb deletions and in the usage of long microhomologies distal to the break site, compared with wild-type (WT) cells. This error-prone repair phenotype could also be revealed by disruption of the Chk2 phosphorylation site of BRCA1, or by expression of a dominant-negative kinase-dead Chk2 mutant in cells with WT BRCA1. We suggest that the differential control of NHEJ subprocesses by BRCA1, in concert with Chk2, reduces the mutagenic potential of NHEJ, thereby contributing to the prevention of familial breast cancers. IS - 3 JF - Cancer research SN - 0008-5472 AD - Department of Radiation Oncology, Vanderbilt University Medical Centre, 1301 22nd Avenue South, Nashville, TN 37232, USA. EP - 1408 TI - Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining. VL - 66 SP - 1401 KW - brca1 KW - damage KW - dna KW - dsb KW - hr KW - nhej KW - repair AU - Zhuang, J AU - Zhang, J AU - Willers, H AU - Wang, H AU - Chung, JH AU - van Gent, DC AU - Hallahan, DE AU - Powell, SN AU - Xia, F PY - 2006/02/01/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-05-3278 ER -