ABSTRACT
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.
Subject(s)
BRCA1 Protein/genetics , Breast Neoplasms/genetics , Cell Cycle Proteins , DNA-Directed DNA Polymerase/metabolism , Neoplasm Proteins/genetics , Ovarian Neoplasms/genetics , Sister Chromatid Exchange , Transcription Factors/genetics , Animals , Ataxia Telangiectasia Mutated Proteins , BRCA2 Protein , DNA Repair , DNA Replication , Eukaryotic Cells , Evolution, Molecular , Female , Humans , Prokaryotic Cells , Protein Serine-Threonine Kinases/metabolism , S PhaseABSTRACT
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.
