DNA recombination, chromosomal stability and carcinogenesis: insights into the role of BRCA2.
Germline mutations affecting a single allele of BRCA2 increase susceptibility to breast and ovarian cancer, whilst germline inheritance of certain bi-allelic mutations causes a Fanconi anaemia-like syndrome. Here, we review current knowledge of the BRCA2 protein, focussing on recent studies that provide mechanistic insight into its biological function in regulating DNA recombination reactions mediated by the RAD51 recombinase. We argue that the chromosomal instability and cancer predisposition provoked by BRCA2 inactivation are a consequence of the failure to re-start stalled DNA replication, and to repair DNA double-strand breaks, through error-free pathways that depend on homologous pairing between DNA strands.
Shivji
Mahmud K K
MK
CR UK Department of Oncology and the Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.
Venkitaraman
Ashok R
AR
D000483:Alleles; D000818:Animals; D024682:BRCA2 Protein / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000648:ultrastructure*; D018360:Crystallography, X-Ray; D004247:DNA / Q000648:ultrastructure*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase; D011995:Recombination, Genetic
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase