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ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks

Author

Listed:
  • Gabriel Balmus

    (University of Cambridge
    Wellcome Trust Sanger Institute
    University of Cambridge)

  • Domenic Pilger

    (University of Cambridge)

  • Julia Coates

    (University of Cambridge)

  • Mukerrem Demir

    (University of Cambridge)

  • Matylda Sczaniecka-Clift

    (University of Cambridge)

  • Ana C. Barros

    (Wellcome Trust Sanger Institute)

  • Michael Woods

    (Wellcome Trust Sanger Institute)

  • Beiyuan Fu

    (Wellcome Trust Sanger Institute)

  • Fengtang Yang

    (Wellcome Trust Sanger Institute)

  • Elisabeth Chen

    (Wellcome Trust Sanger Institute)

  • Matthias Ostermaier

    (Institute of Molecular Biology (IMB))

  • Tatjana Stankovic

    (University of Birmingham)

  • Hannes Ponstingl

    (Wellcome Trust Sanger Institute)

  • Mareike Herzog

    (University of Cambridge
    Wellcome Trust Sanger Institute)

  • Kosuke Yusa

    (Wellcome Trust Sanger Institute)

  • Francisco Munoz Martinez

    (University of Cambridge)

  • Stephen T. Durant

    (AstraZeneca)

  • Yaron Galanty

    (University of Cambridge)

  • Petra Beli

    (Institute of Molecular Biology (IMB))

  • David J. Adams

    (Wellcome Trust Sanger Institute)

  • Allan Bradley

    (Wellcome Trust Sanger Institute)

  • Emmanouil Metzakopian

    (Wellcome Trust Sanger Institute
    University of Cambridge)

  • Josep V. Forment

    (University of Cambridge
    AstraZeneca)

  • Stephen P. Jackson

    (University of Cambridge)

Abstract

Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.

Suggested Citation

  • Gabriel Balmus & Domenic Pilger & Julia Coates & Mukerrem Demir & Matylda Sczaniecka-Clift & Ana C. Barros & Michael Woods & Beiyuan Fu & Fengtang Yang & Elisabeth Chen & Matthias Ostermaier & Tatjana, 2019. "ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07729-2
    DOI: 10.1038/s41467-018-07729-2
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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. Junho Kim & August Yue Huang & Shelby L. Johnson & Jenny Lai & Laura Isacco & Ailsa M. Jeffries & Michael B. Miller & Michael A. Lodato & Christopher A. Walsh & Eunjung Alice Lee, 2022. "Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Qin Li & Jincong Zhou & Shuai Li & Weifeng Zhang & Yingxue Du & Kuan Li & Yingxiang Wang & Qianwen Sun, 2023. "DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Hanrui Zhang & Julian Kreis & Sven-Eric Schelhorn & Heike Dahmen & Thomas Grombacher & Michael Zühlsdorf & Frank T. Zenke & Yuanfang Guan, 2023. "Mapping combinatorial drug effects to DNA damage response kinase inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    5. Diana Rubio-Contreras & Fernando Gómez-Herreros, 2023. "TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.

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