Chromosomal instability and cancer predisposition: insights from studies on the breast cancer susceptibility gene BRCA2
- A Venkitaraman1
© BioMed Central Ltd 2001
Received: 10 May 2001
Published: 31 May 2001
Inherited mutations in the breast cancer susceptibility gene BRCA2 predispose to breast, ovarian and other cancers. BRCA2 encodes a 3418-amino-acid protein that localizes to the nucleus of dividing cells. The biological functions of the protein and its role in tumour suppression remain uncertain.
We have identified an essential function for BRCA2 in DNA repair by homologous recombination. In BRCA2-deficient cells, DNA breaks introduced into chromosomal substrates are inefficiently repaired by homology-directed mechanisms, although repair by nonhomologous end-joining is unaffected. BRCA2 interacts with the RAD51 recombination protein, a functional homolog of bacterial RecA. The correct intracellular localization and function of RAD51 are dependent upon BRCA2, suggesting a mechanistic basis for its role in repair.
Loss of BRCA2 induces chromosomal instability characterized by spontaneous breakage, in appropriate mitotic exchanges and chromosomal fusions. Evidence will be presented that the repair of DNA breaks that arise spontaneously during DNA replication require BRCA2 for their error-free resolution. Loss of this function may foster carcinogenesis by increasing the rate of spontaneous mutation.
Paradoxically, BRCA2-deficient cells undergo cell cycle arrest rather than the unrestrained proliferation that is typical of neoplastic transformation. We find that mutations inactivating cell cycle checkpoints that regulate assembly of the mitotic spindle reverse proliferative arrest, and foster transformation, in BRCA2-deficient cells. These findings have implications not only for the evolution of tumours following BRCA2 loss, but also for the mechanisms by which cells perceive and respond to chromosome breakage.