The role of BRCA1 in non-homologous end-joining

From the genotypic viewpoint, single nucleotide polymorphisms in the genes of the non-homologous end-joining (NHEJ) pathway, which is important in the repair of DNA double-strand breaks, have been shown to be associated with increased breast cancer risk. However, more phenotypic evidence is needed to strengthen the link between defective NHEJ genes and breast cancer development. Recently, BRCA1-deficient mouse embryonic fibroblasts were found to have significantly reduced NHEJ activity, suggesting an accessory role of BRCA1 in NHEJ. Since BRCA1 is a well-documented breast cancer susceptibility gene, this association between NHEJ and BRCA1 not only suggests a role of BRCA1 in NHEJ, but also provides support for the tumorigenic contribution of the NHEJ pathway to breast cancer development. Interestingly, the phenotypic data show that BRCA1 may promote only specific subtypes of NHEJ, e.g. in vivo precise and terminal end-joining capacities, and have either a suppressive or no effect on others. However, these findings have remained inconclusive, and the lack of consistency between these results may be at least partly explained by the use of different assays, which may measure different subtypes of NHEJ, and of different cell lines investigated. Although some insights have been obtained, the whole picture of NHEJ repair in mammalian cells is far from complete, and the questions of how many subpathways are involved or how we can investigate each subpathway have not yet been adequately addressed.