RESUMO
Heritable predisposition to breast and/or ovarian cancer is determined, in part, by germline mutation affecting one of two tumor suppressor genes, BRCA1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995). These genes are required for the maintenance of genomic integrity and for control of homologous recombination in somatic and meiotic cells. Here, we explore the hypothesis that a major role of the BRCA gene products in the somatic DNA damage response centers upon the control of recombination between sister chromatids during S phase. By analogy with model organisms, we suggest that stalling of a mammalian DNA polymerase complex by its encounter with abnormal DNA structure calls forth a series of responses that collaborate to enforce appropriate recombinational outcomes, and to suppress inappropriate or 'illegitimate' recombination.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Proteínas de Ciclo Celular , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Troca de Cromátide Irmã , Fatores de Transcrição/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteína BRCA2 , Reparo do DNA , Replicação do DNA , Células Eucarióticas , Evolução Molecular , Feminino , Humanos , Células Procarióticas , Proteínas Serina-Treonina Quinases/metabolismo , Fase SRESUMO
Retrovirally expressed, wild-type BRCA1 decreased the gamma radiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair (DSBR) of the BRCA1-/- human breast cancer line, HCC1937. It also reduced its susceptibility to DSB generation by IR. By contrast, multiple, clinically validated, missense mutant BRCA1 products were nonfunctional in these assays. These data constitute the basis for a BRCA1 functional assay and suggest that efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression function.
