![]() Germ line mutations in BRCA1 predispose to breast cancers and other tumors. However, little is known about the genetic factors that control the extent of sequence alteration during error-prone repair or that prevent error-prone repair mechanisms in scenarios where precise end-joining is a potentially available repair pathway. Given that any deletion arising from the break site may destroy coding or regulatory sequences, or may lead to chromosomal aberrations and thereby increase genomic instability, NHEJ processes must be closely regulated to limit the resulting mutagenic potential. This error-prone type of rejoining typically involves end modification (which can be limited with loss or insertion of a few nucleotides) or extensive (with deletions up to hundreds of nucleotides). Alternatively, if error-free end-joining is not an option (e.g., ionizing radiation–induced DSBs or restriction endonuclease–induced noncompatible ends), end-joining is error-prone. It has been shown recently that NHEJ can precisely religate DNA ends without sequence change if the ends are cohesive and complementary or blunt. In contrast, NHEJ, which is traditionally considered error-prone, reseals DSBs efficiently throughout all cell cycle phases with very limited or no homology requirements ( 4). ![]() ![]() HR is most active in the late S and G 2 phases of cell cycle. HR is typically error-free and requires extensive homology on a sister chromatid or a homologous chromosome, which may serve as repair templates to faithfully restore the original DNA sequence ( 3). DSBs, which can be lethal if unrepaired or mutagenic if misrepaired, can be removed from the genome by two general types of genetically largely independent repair mechanisms-homologous recombination (HR) or nonhomologous end-joining (NHEJ). (Cancer Res 2006 66(3): 1401-8)Ĭhromosomal double-strand breaks (DSBs), which may arise during physiologic processes, such as replication or V(D)J recombination, or after cellular exposure to ionizing radiation and chemotherapy, are the most dangerous form of DNA lesions ( 1, 2). 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. 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. 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. 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. However, the precise role of BRCA1 in regulating these different subtypes of NHEJ is not clear. 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). Through its interactions with the checkpoint kinase 2 (Chk2) kinase and Rad51, BRCA1 promotes homologous recombination, which is typically an error-free repair process. The tumor suppressor gene BRCA1 maintains genomic integrity by protecting cells from the deleterious effects of DNA double-strand breaks (DSBs).
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