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

  • Mol Cell. 2021 Aug 5;81(15):3128-3144.e7. doi: 10.1016/j.molcel.2021.06.011.
Ke Cong  1 ,  Min Peng  1 ,  Arne Nedergaard Kousholt  2 ,  Wei Ting C Lee  3 ,  Silviana Lee  1 ,  Sumeet Nayak  1 ,  John Krais  4 ,  Pamela S VanderVere-Carozza  5 ,  Katherine S Pawelczak  6 ,  Jennifer Calvo  1 ,  Nicholas J Panzarino  1 ,  John J Turchi  7 ,  Neil Johnson  4 ,  Jos Jonkers  2 ,  Eli Rothenberg  3 ,  Sharon B Cantor  8
Affiliations
  • 1. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 2. Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
  • 3. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
  • 4. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 6. NERx Biosciences, 212 W. 10th St., Suite A480, Indianapolis, IN 46202, USA.
  • 7. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; NERx Biosciences, 212 W. 10th St., Suite A480, Indianapolis, IN 46202, USA.
  • 8. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].
PMID: 34216544 DOI: 10.1016/j.molcel.2021.06.011
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.

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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