Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

Ke Cong, Min Peng, Arne Nedergaard Kousholt, Wei Ting C. Lee, Silviana Lee, Sumeet Nayak, John Krais, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Jennifer Calvo, Nicholas J. Panzarino, John J. Turchi, Neil Johnson, Jos Jonkers, Eli Rothenberg, Sharon B. Cantor

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions.

Original languageEnglish
Pages (from-to)3128-3144.e7
JournalMolecular cell
Volume81
Issue number15
DOIs
StatePublished - Aug 5 2021

Keywords

  • BRCA1/BRCA2
  • Fanconi anemia (FA)
  • Okazaki fragment processing
  • PARP inhibitor
  • fork protection
  • homologous recombination
  • parylation
  • replication gaps
  • ssDNA
  • synthetic lethal

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