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Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or "BRCAness" could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps. Cong and Cantor highlight that PARP inhibition (PARPi) is synthetic lethal with BRCA -mutated cancer due to a toxic level of DNA replication gaps that they propose stem from combined lagging strand synthesis defects. They further propose that lagging strand gaps are an unappreciated consequence of other toxic combinations and anticancer drugs. [ABSTRACT FROM AUTHOR]

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target. [Display omitted] • LIG3 is a critical suppressor of PARPi toxicity in BRCA1−/−53BP1−/− cells • Enhanced PARPi toxicity by LIG3 depletion requires BRCA1 loss but not HR deficiency • LIG3 loss induces MRE11-mediated ssDNA gaps in BRCA1−/−53BP1−/− cells exposed to PARPi • LIG3 depletion enhances efficacy of PARPi against BRCA1-deficient mouse mammary tumors Paes Dias et al. report that loss of nuclear LIG3 increases PARPi toxicity in BRCA1/53BP1 double-deficient cells by promoting the formation of MRE11-mediated post-replicative ssDNA gaps, leading to accumulation of chromosomal abnormalities. LIG3 depletion also enhances the efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)