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

Nat Struct Mol Biol. 2010 Jun;17(6):688-95. doi: 10.1038/nsmb.1831. Epub 2010 May 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Comment

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Proliferation
  • Chromosomal Proteins, Non-Histone
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / physiology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Female
  • Gene Deletion
  • Genes, BRCA1*
  • Genes, BRCA2
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mutagenesis, Insertional
  • Mutation*
  • Tumor Cells, Cultured
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Apoptosis Regulatory Proteins
  • BLID protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • TP53BP1 protein, human
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1