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

Author

Listed:
  • Stephen J. Pettitt

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Dragomir B. Krastev

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Inger Brandsma

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Amy Dréan

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Feifei Song

    (The Institute of Cancer Research
    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
    The Institute of Cancer Research)

  • Rachel Brough

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • James Campbell

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Jessica Frankum

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Michael Ranes

    (The Institute of Cancer Research)

  • Helen N. Pemberton

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Rumana Rafiq

    (The Institute of Cancer Research
    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
    The Institute of Cancer Research)

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.

Suggested Citation

  • 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 & Michae, 2018. "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03917-2
    DOI: 10.1038/s41467-018-03917-2
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    Cited by:

    1. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Ke Cong & Nathan MacGilvary & Silviana Lee & Shannon G. MacLeod & Jennifer Calvo & Min Peng & Arne Nedergaard Kousholt & Tovah A. Day & Sharon B. Cantor, 2024. "FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Simon D. Schwarz & Jianming Xu & Kapila Gunasekera & David Schürmann & Cathrine B. Vågbø & Elena Ferrari & Geir Slupphaug & Michael O. Hottiger & Primo Schär & Roland Steinacher, 2024. "Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Diego Dibitetto & Martin Liptay & Francesca Vivalda & Hülya Dogan & Ewa Gogola & Martín González Fernández & Alexandra Duarte & Jonas A. Schmid & Morgane Decollogny & Paola Francica & Sara Przetocka &, 2024. "H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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