53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.
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.
Bouwman
Peter
P
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Aly
Amal
A
Escandell
Jose M
JM
Pieterse
Mark
M
Bartkova
Jirina
J
van der Gulden
Hanneke
H
Hiddingh
Sanne
S
Thanasoula
Maria
M
Kulkarni
Atul
A
Yang
Qifeng
Q
Haffty
Bruce G
BG
Tommiska
Johanna
J
Blomqvist
Carl
C
Drapkin
Ronny
R
Adams
David J
DJ
Nevanlinna
Heli
H
Bartek
Jiri
J
Tarsounas
Madalena
M
Ganesan
Shridar
S
Jonkers
Jos
J
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics*; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009154:Mutation; D014407:Tumor Cells, Cultured; D000071857:Tumor Suppressor p53-Binding Protein 1
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1
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