TY - JOUR
T1 - Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency
AU - Cong, Ke
AU - Peng, Min
AU - Kousholt, Arne Nedergaard
AU - Lee, Wei Ting C.
AU - Lee, Silviana
AU - Nayak, Sumeet
AU - Krais, John
AU - VanderVere-Carozza, Pamela S.
AU - Pawelczak, Katherine S.
AU - Calvo, Jennifer
AU - Panzarino, Nicholas J.
AU - Turchi, John J.
AU - Johnson, Neil
AU - Jonkers, Jos
AU - Rothenberg, Eli
AU - Cantor, Sharon B.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8/5
Y1 - 2021/8/5
N2 - 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.
AB - 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.
KW - BRCA1/BRCA2
KW - Fanconi anemia (FA)
KW - Okazaki fragment processing
KW - PARP inhibitor
KW - fork protection
KW - homologous recombination
KW - parylation
KW - replication gaps
KW - ssDNA
KW - synthetic lethal
UR - http://www.scopus.com/inward/record.url?scp=85111585473&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2021.06.011
DO - 10.1016/j.molcel.2021.06.011
M3 - Article
C2 - 34216544
AN - SCOPUS:85111585473
SN - 1097-2765
VL - 81
SP - 3128-3144.e7
JO - Molecular cell
JF - Molecular cell
IS - 15
ER -