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Symposium 9: Genomic Instability and Cancer

Cancer susceptibility and the functions of the BRCA2 tumor suppressor

University of Cambridge, Cambridge, United Kingdom

Abstract

SY09-3

Inherited mutations affecting the BRCA2 breast cancer susceptibility protein predispose to breast, ovarian and other epithelial cancers at high penetrance (reviewed in 1). BRCA2 inactivation provokes the spontaneous instability of chromosome structure in dividing cells, leading to gross chromosomal rearrangements such as translocations and deletions (2,3). How BRCA2 protects chromosome structure is incompletely understood. We have elucidated an important function of BRCA2 in the regulation of the enzyme RAD51 in reactions that lead to DNA recombination between homologous DNA strands (4, 5). These reactions might be particularly essential in overcoming blocks to DNA replication by DNA damage, depleted nucleotide pools, or template-bound proteins. Indeed, we find that in BRCA2-deficient cells, DNA intermediates at stalled DNA replication forks are de-stabilized during genome-wide replication arrest, accompanied by the accumulation of genome-wide double-strand DNA breaks (6). This suggests that in BRCA2 deficiency, it is the breakdown of replication forks, which arrest or pause during normal cell growth, that triggers spontaneous DNA breakage, leading to mutability and cancer predisposition. Besdies chromosomal structural aberrations, BRCA2-deficient cells also exhibit aneuploidy with gains in chromosome number (2). Suggestive of functions during mitosis, BRCA2 is phosphorylated by the chromosome passenger protein Plk1 during transit through the G2/M phases (7). Cytokinesis is delayed in BRCA2-deficient cells, with accumulation at the cleavage and abscission steps, accompanied by abnormalities in the distribution of proteins that form the actomyosin contractile ring (8). These findings link BRCA2 inactivation to cytokinetic abnormalities, and raise the possibility that BRCA2 may have functions at late stages during mitosis.