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CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks

Author

Listed:
  • Magdalena B. Rother

    (Leiden University Medical Center)

  • Stefania Pellegrino

    (University of Zurich)

  • Rebecca Smith

    (Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)—UMR 6290)

  • Marco Gatti

    (University of Zurich)

  • Cornelia Meisenberg

    (The Institute of Cancer Research, Royal Cancer Hospital)

  • Wouter W. Wiegant

    (Leiden University Medical Center)

  • Martijn S. Luijsterburg

    (Leiden University Medical Center)

  • Ralph Imhof

    (University of Zurich)

  • Jessica A. Downs

    (The Institute of Cancer Research, Royal Cancer Hospital)

  • Alfred C. O. Vertegaal

    (Leiden University Medical Center)

  • Sébastien Huet

    (Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)—UMR 6290
    Institut Universitaire de France)

  • Matthias Altmeyer

    (University of Zurich)

  • Haico van Attikum

    (Leiden University Medical Center)

Abstract

Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially regulate DNA repair pathways is insufficiently understood. Here, we identify the Chromodomain Helicase DNA Binding Protein 7 (CHD7), which is frequently mutated in CHARGE syndrome, as an integral component of the non-homologous end-joining (NHEJ) DSB repair pathway. Upon recruitment via PARP1-triggered chromatin remodeling, CHD7 stimulates further chromatin relaxation around DNA break sites and brings in HDAC1/2 for localized chromatin de-acetylation. This counteracts the CHD7-induced chromatin expansion, thereby ensuring temporally and spatially controlled ‘chromatin breathing’ upon DNA damage, which we demonstrate fosters efficient and accurate DSB repair by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent cNHEJ reinforces 53BP1 assembly at the damaged chromatin and shifts DSB repair to mutagenic NHEJ, revealing a backup function of 53BP1 when cNHEJ fails.

Suggested Citation

  • Magdalena B. Rother & Stefania Pellegrino & Rebecca Smith & Marco Gatti & Cornelia Meisenberg & Wouter W. Wiegant & Martijn S. Luijsterburg & Ralph Imhof & Jessica A. Downs & Alfred C. O. Vertegaal & , 2020. "CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19502-5
    DOI: 10.1038/s41467-020-19502-5
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    Cited by:

    1. Caojie Liu & Qiuchan Xiong & Qiwen Li & Weimin Lin & Shuang Jiang & Danting Zhang & Yuan Wang & Xiaobo Duan & Ping Gong & Ning Kang, 2022. "CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Jenny Kaur Singh & Rebecca Smith & Magdalena B. Rother & Anton J. L. Groot & Wouter W. Wiegant & Kees Vreeken & Ostiane D’Augustin & Robbert Q. Kim & Haibin Qian & Przemek M. Krawczyk & Román González, 2021. "Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining," Nature Communications, Nature, vol. 12(1), pages 1-21, December.

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