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Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks

Author

Listed:
  • Pauline Chanut

    (Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS
    Equipe labellisée Ligue Nationale Contre le Cancer)

  • Sébastien Britton

    (Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS
    Equipe labellisée Ligue Nationale Contre le Cancer
    The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge)

  • Julia Coates

    (The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge)

  • Stephen P. Jackson

    (The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge
    The Wellcome Trust Sanger Institute)

  • Patrick Calsou

    (Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS
    Equipe labellisée Ligue Nationale Contre le Cancer)

Abstract

Repair of single-ended DNA double-strand breaks (seDSBs) by homologous recombination (HR) requires the generation of a 3′ single-strand DNA overhang by exonuclease activities in a process called DNA resection. However, it is anticipated that the highly abundant DNA end-binding protein Ku sequesters seDSBs and shields them from exonuclease activities. Despite pioneering works in yeast, it is unclear how mammalian cells counteract Ku at seDSBs to allow HR to proceed. Here we show that in human cells, ATM-dependent phosphorylation of CtIP and the epistatic and coordinated actions of MRE11 and CtIP nuclease activities are required to limit the stable loading of Ku on seDSBs. We also provide evidence for a hitherto unsuspected additional mechanism that contributes to prevent Ku accumulation at seDSBs, acting downstream of MRE11 endonuclease activity and in parallel with MRE11 exonuclease activity. Finally, we show that Ku persistence at seDSBs compromises Rad51 focus assembly but not DNA resection.

Suggested Citation

  • Pauline Chanut & Sébastien Britton & Julia Coates & Stephen P. Jackson & Patrick Calsou, 2016. "Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12889
    DOI: 10.1038/ncomms12889
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    Cited by:

    1. Huimin Zhang & Yun Xiong & Dan Su & Chao Wang & Mrinal Srivastava & Mengfan Tang & Xu Feng & Min Huang & Zhen Chen & Junjie Chen, 2022. "TDP1-independent pathways in the process and repair of TOP1-induced DNA damage," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. 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.
    3. Ashna Dhoonmoon & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Anastasia Hale & Ashna Dhoonmoon & Joshua Straka & Claudia M. Nicolae & George-Lucian Moldovan, 2023. "Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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