Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

Stephen J. Pettitt, Dragomir B. Krastev, Inger Brandsma, Amy Dréan, Feifei Song, Radoslav Aleksandrov, Maria I. Harrell, Malini Menon, Rachel Brough, James Campbell, Jessica Frankum, Michael Ranes, Helen N. Pemberton, Rumana Rafiq, Kerry Fenwick, Amanda Swain, Sebastian Guettler, Jung-Min Lee, Elizabeth M. Swisher, Stoyno Stoynov, Kosuke Yusa, Alan Ashworth () and Christopher J. Lord ()
Additional contact information
Stephen J. Pettitt: The Institute of Cancer Research
Dragomir B. Krastev: The Institute of Cancer Research
Inger Brandsma: The Institute of Cancer Research
Amy Dréan: The Institute of Cancer Research
Feifei Song: The Institute of Cancer Research
Radoslav Aleksandrov: Bulgarian Academy of Sciences
Maria I. Harrell: University of Washington School of Medicine
Malini Menon: The Institute of Cancer Research
Rachel Brough: The Institute of Cancer Research
James Campbell: The Institute of Cancer Research
Jessica Frankum: The Institute of Cancer Research
Michael Ranes: The Institute of Cancer Research
Helen N. Pemberton: The Institute of Cancer Research
Rumana Rafiq: The Institute of Cancer Research
Kerry Fenwick: The Institute of Cancer Research
Amanda Swain: The Institute of Cancer Research
Sebastian Guettler: The Institute of Cancer Research
Jung-Min Lee: National Cancer Institute
Elizabeth M. Swisher: University of Washington School of Medicine
Stoyno Stoynov: Bulgarian Academy of Sciences
Kosuke Yusa: Wellcome Trust Sanger Institute
Alan Ashworth: UCSF Helen Diller Family Comprehensive Cancer Center
Christopher J. Lord: The Institute of Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 “tag-mutate-enrich” mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro and in vivo PARPi resistance. Mutations both within and outside of the PARP1 DNA-binding zinc-finger domains cause PARPi resistance and alter PARP1 trapping, as does a PARP1 mutation found in a clinical case of PARPi resistance. This reinforces the importance of trapped PARP1 as a cytotoxic DNA lesion and suggests that PARP1 intramolecular interactions might influence PARPi-mediated cytotoxicity. PARP1 mutations are also tolerated in cells with a pathogenic BRCA1 mutation where they result in distinct sensitivities to chemotherapeutic drugs compared to other mechanisms of PARPi resistance (BRCA1 reversion, 53BP1, REV7 (MAD2L2) mutation), suggesting that the underlying mechanism of PARPi resistance that emerges could influence the success of subsequent therapies.

Date: 2018
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DOI: 10.1038/s41467-018-03917-2

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