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

Joseph Nacson, John J. Krais, Andrea J. Bernhardy, Emma Clausen, Wanjuan Feng, Yifan Wang, Emmanuelle Nicolas, Kathy Q. Cai, Rossella Tricarico, Xiang Hua, Daniela DiMarcantonio, Esteban Martinez, Dali Zong, Elizabeth A. Handorf, Alfonso Bellacosa, Joseph R. Testa, Andre Nussenzweig, Gaorav P. Gupta, Stephen M. Sykes, Neil Johnson

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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. Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2.

Original languageEnglish
Pages (from-to)3513-3527.e7
JournalCell Reports
Volume24
Issue number13
DOIs
StatePublished - Sep 25 2018

Keywords

  • 53BP1
  • BRCA1
  • PARP inhibitors
  • homologous recombination
  • resistance

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