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

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

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

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 signalsga 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 dysfunctionginduced 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.

Original languageEnglish (US)
Pages (from-to)1461-1469
Number of pages9
JournalNature Structural and Molecular Biology
Volume17
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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