53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers

Peter Bouwman, Amal Aly, Jose M. Escandell, Mark Pieterse, Jirina Bartkova, Hanneke Van Der Gulden, Sanne Hiddingh, Maria Thanasoula, Atul Kulkarni, Qifeng Yang, Bruce G. Haffty, Johanna Tommiska, Carl Blomqvist, Ronny Drapkin, David J. Adams, Heli Nevanlinna, Jiri Bartek, Madalena Tarsounas, Shridar Ganesan, Jos Jonkers

Research output: Contribution to journalArticlepeer-review

617 Scopus citations

Abstract

Germ-line mutations in breast cancer 1, early onset (BRCA1) result in predisposition to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify p53-binding protein 1 (53BP1) as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell-cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Notably, loss of 53BP1 partially restores the homologous-recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.

Original languageEnglish (US)
Pages (from-to)688-695
Number of pages8
JournalNature Structural and Molecular Biology
Volume17
Issue number6
DOIs
StatePublished - Jun 2010

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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