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

Peter Bouwman | Zendy; Amal Aly | Zendy; José Miguel Escandell | Zendy; Mark Pieterse | Zendy; Jiřina Bártková | Zendy; Hanneke van der Gulden | Zendy; Sanne Hiddingh | Zendy; Maria Thanasoula | Zendy; Atul Kulkarni | Zendy; Qifeng Yang | Zendy; Bruce G. Haffty | Zendy; Johanna Tommiska | Zendy; Carl Blomqvist | Zendy; Ronny Drapkin | Zendy; David J. Adams | Zendy; Heli Nevanlinna | Zendy; Jiří Bártek | Zendy; Madalena Tarsounas | Zendy; Shridar Ganesan | Zendy; Jos Jonkers | Zendy

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

Author(s) -

Peter Bouwman,

Amal Aly,

José Miguel Escandell,

Mark Pieterse,

Jiřina Bártková,

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,

Jiří Bártek,

Madalena Tarsounas,

Shridar Ganesan,

Jos Jonkers

Publication year - 2010

Publication title -

nature structural and molecular biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 9.448

H-Index - 270

eISSN - 1545-9993

pISSN - 1545-9985

DOI - 10.1038/nsmb.1831

Subject(s) - cancer research , genome instability , homologous recombination , dna damage , brca2 protein , cell cycle checkpoint , biology , mutation , dna repair , chek1 , breast cancer , triple negative breast cancer , g2 m dna damage checkpoint , poly adp ribose polymerase , cell cycle , microbiology and biotechnology , germline mutation , cancer , genetics , dna , gene , polymerase

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.

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