Rapid recruitment of BRCA1 to DNA double-strand breaks is dependent on its association with Ku80

Leizhen Wei, Li Lan, Zehui Hong, Akira Yasui, Chikashi Ishioka, Natsuko Chiba

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

BRCA1 is the first susceptibility gene to be linked to breast and ovarian cancers. Although mounting evidence has indicated that BRCA1 participates in DNA double-strand break (DSB) repair pathways, its precise mechanism is still unclear. Here, we analyzed the in situ response of BRCA1 at DSBs produced by laser microirradiation. The amino (N)- and carboxyl (C)-terminal fragments of BRCA1 accumulated independently at DSBs with distinct kinetics. The N-terminal BRCA1 fragment accumulated immediately after laser irradiation at DSBs and dissociated rapidly. In contrast, the C-terminal fragment of BRCA1 accumulated more slowly at DSBs but remained at the sites. Interestingly, rapid accumulation of the BRCA1 N terminus, but not the C terminus, at DSBs depended on Ku80, which functions in the nonhomologous end-joining (NHEJ) pathway, independently of BARD1, which binds to the N terminus of BRCA1. Two small regions in the N terminus of BRCA1 independently accumulated at DSBs and interacted with Ku80. Missense mutations found within the N terminus of BRCA1 in cancers significantly changed the kinetics of its accumulation at DSBs. A P142H mutant failed to associate with Ku80 and restore resistance to irradiation in BRCA1-deficient cells. These might provide a molecular basis of the involvement of BRCA1 in the NHEJ pathway of the DSB repair process.

Original languageEnglish
Pages (from-to)7380-7393
Number of pages14
JournalMolecular and cellular biology
Volume28
Issue number24
DOIs
Publication statusPublished - 2008 Dec

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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