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Cong K , Peng M , Kousholt AN , Lee WTC , Lee S , Nayak S , Krais J , VanderVere-Carozza PS , Pawelczak KS , Calvo J , Panzarino NJ , Jonkers J , Johnson N , Turchi JJ , Rothenberg E , Cantor SB
Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency
Mol Cell. 2021 Aug 5;81(15) :3128-3144 e7
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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.
Notes
1097-4164 Cong, Ke Peng, Min Kousholt, Arne Nedergaard Lee, Wei Ting C Lee, Silviana Nayak, Sumeet Krais, John VanderVere-Carozza, Pamela S Pawelczak, Katherine S Calvo, Jennifer Panzarino, Nicholas J Jonkers, Jos Johnson, Neil Turchi, John J Rothenberg, Eli Cantor, Sharon B R01 CA214799/CA/NCI NIH HHS/United States R01 GM135293/GM/NIGMS NIH HHS/United States Journal Article United States Mol Cell. 2021 Jun 26:S1097-2765(21)00458-5. doi: 10.1016/j.molcel.2021.06.011.