Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis

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Abstract
Homologous recombination maintains genomic stability in mammalian mitotic cells through precise templated repair of DNA double-strand breaks and other lesions. The outcome of homologous recombination is typically precise when the sister chromatid is the donor template. Homologous recombination is a coordinated process involving the RAD51 strand exchange protein and numerous other proteins that promote RAD51 function. RAD51 forms a filament on single-stranded DNA that is generated by end resection. Precise repair is promoted by both regulated expression and activation of factors involved in homologous repair during the S and G2 phases of the cell cycle. Alternative templates for repair that encompass some degree of heterology have the potential to be mutagenic, with the occurrence of loss of heterozygosity or rearrangements. Most rearrangements occur by alternative DNA double-strand break repair pathways that do not involve homology. Mammalian cells that are defective for homologous recombination components have spontaneous and damage-induced genomic instability, mild ionizing radiation sensitivity and severe sensitivity to DNA cross-linking agents. In humans, biallelic defects in the homologous recombination factors breast and ovarian cancer type 2 susceptibility protein (BRCA2), partner and localizer of BRCA2 (PALB2) and BRCA1-interacting protein 1 (BRIP1) result in Fanconi anaemia, and mono-allelic defects in BRCA2, BRCA1, PALB2 and BRIP1 result in a predisposition to breast cancer. Other human tumours are associated with the loss of BRCA2, BRCA1 and PALB2.