In search of the tumour-suppressor functions of BRCA1 and BRCA2

Abstract

Hereditary breast and ovarian cancer syndromes can be caused by loss-of-function germline mutations in one of two tumour-suppressor genes, BRCA1 and BRCA2 (ref. 1). Each gene product interacts with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure. However, it is unclear to what extent such functions specifically suppress breast and ovarian cancer. Here we analyse what is known of BRCA gene function and highlight some unanswered questions in the field.

Figure 1

Structure and localization of BRCA proteins. a, Structure of the BRCA1 and BRCA2 polypeptides. BRCA1 shows RING domain, BRCT motifs, implicated in DNA damage response pathways. BRCA2 shows BRC repeats, involved in the Rad51 interaction. Some associated proteins are denoted in blue. b, Localization of BRCA1 during meiotic prophase I. Depicted is a single primary, human spermatocyte nucleus, stained with an antibody to the synaptonemal complex protein, SCP3 (white), and with BRCA1 antibody (red). BRCA1 localizes to the unsynapsed regions (axial elements) of developing synaptonemal complexes. Copyright held by Cell Press, reproduced with permission.

Figure 2

Checkpoint inactivation and BRCA gene-mediated tumorigenesis. Inactivation of DNA damage-responsive cell cycle checkpoints may contribute to the cellular response to BRCA gene dysfunction. Loss of BRCA function and associated chromosome breakage in a cell trigger checkpoints that deselect it. If such a checkpoint has already been disabled (as in a pre-cancerous cell), the chromosome breakage syndrome may be tolerated and lead to accelerated neoplastic progression.

Figure 3

Proposed role for the BRCA proteins in sister chromatid recombination. DNA polymerase stalling activates S-phase checkpoint signalling and recruits BRCA1, BRCA2, Rad51 and associated proteins to sites of arrested DNA synthesis. We propose that this recruitment arises from the existence of tracts of persistent ssDNA close to a replication fork. Such lesions, or their derivatives, may activate S-phase checkpoint signalling and act as a substrate for BRCA protein-mediated recombinational repair.