Journal Article

BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping

Gallardo, Maria M, Suram, Anitha, Jaco, Isabel, Thanasoula, Maria, Carlos, Ana Rita, Benitez, Javier, Jonkers, Jos, Escandell, Jose M, Tarsounas, Madalena, Herbig, Utz, Bouwman, Peter, Badie, Sophie, Blasco, Maria A

2010

Overview

Mutations in BRCA2 are associated with higher susceptibility to some forms of cancer. BRCA2 is known to play a central role in the repair of DNA breaks via homologous recombination. Now a role for BRCA2 in telomere integrity is revealed, indicating that BRCA2 can contribute to genome stability in multiple ways. The tumor suppressor protein BRCA2 is a key component of the homologous recombination pathway of DNA repair, acting as the loader of RAD51 recombinase at sites of double-strand breaks. Here we show that BRCA2 associates with telomeres during the S and G2 phases of the cell cycle and facilitates the loading of RAD51 onto telomeres. Conditional deletion of Brca2 and inhibition of Rad51 in mouse embryonic fibroblasts (MEFs), but not inactivation of Brca1 , led to shortening of telomeres and accumulation of fragmented telomeric signals—a hallmark of telomere fragility that is associated with replication defects. These findings suggest that BRCA2-mediated homologous recombination reactions contribute to the maintenance of telomere length by facilitating telomere replication and imply that BRCA2 has an essential role in maintaining telomere integrity during unchallenged cell proliferation. Mouse mammary tumors that lacked Brca2 accumulated telomere dysfunction–induced foci. Human breast tumors in which BRCA2 was mutated had shorter telomeres than those in which BRCA1 was mutated, suggesting that the genomic instability in BRCA2 -deficient tumors was due in part to telomere dysfunction.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/211 / 631/337/103/560 / 631/337/1427/2190 / 631/67/1347 / Animals / Biochemistry / Biological Microscopy / Biomedical and Life Sciences / BRCA mutations / BRCA2 Protein - genetics / BRCA2 Protein - metabolism / BRCA2 Protein - physiology / Breast cancer / Care and treatment / Cell cycle / Cells, Cultured / Chromatin Immunoprecipitation / Deoxyribonucleic acid / DNA / DNA Repair / G2 Phase / Gene Deletion / Genetic aspects / Genomic Instability / Genomics / Health aspects / Inactivation / Life Sciences / Membrane Biology / Mice / Physiological aspects / Protein Structure / Proteins / Rad51 Recombinase - antagonists & inhibitors / Rad51 Recombinase - genetics / Rad51 Recombinase - metabolism / Risk factors / Rodents / S Phase / Telomere - chemistry / Telomere - metabolism / Telomeres / Tumors