BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

Cell Rep. 2018 Sep 25;24(13):3513-3527.e7. doi: 10.1016/j.celrep.2018.08.086.


BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1-/- mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance.

Keywords: 53BP1; BRCA1; PARP inhibitors; homologous recombination; resistance.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Drug Resistance, Neoplasm*
  • Fanconi Anemia Complementation Group N Protein / metabolism
  • Female
  • HEK293 Cells
  • Homologous Recombination*
  • Humans
  • Loss of Function Mutation
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / genetics*
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Rad51 Recombinase / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / genetics*
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor p53-Binding Protein 1
  • RAD51 protein, human
  • Rad51 Recombinase