DNA polymerase stalling, sister chromatid recombination and the BRCA genes

Heritable predisposition to breast and/or ovarian cancer is determined, in part, by germline mutation affecting one of two tumor suppressor genes, BRC A1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995). These genes are req uired for the maintenance of genomic integrity and for control of homologou s recombination in somatic and meiotic cells. Here, we explore the hypothes is that a major role of the BRCA gene products in the somatic DNA damage re sponse centers upon the control of recombination between sister chromatids during S phase. By analogy with model organisms, we suggest that stalling o f a mammalian DNA polymerase complex by its encounter with abnormal DNA str ucture calls forth a series of responses that collaborate to enforce approp riate recombinational outcomes, and to suppress inappropriate or 'illegitim ate' recombination.