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, 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.
Scully
R
R
Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Puget
N
N
Vlasakova
K
K
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D005057:Eukaryotic Cells; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D011387:Prokaryotic Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase; D012854:Sister Chromatid Exchange; D014157:Transcription Factors / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004259:DNA-Directed DNA Polymerase