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ATR is a multifunctional regulator of male mouse meiosis

Author

Listed:
  • Alexander Widger

    (The Francis Crick Institute)

  • Shantha K. Mahadevaiah

    (The Francis Crick Institute)

  • Julian Lange

    (Memorial Sloan Kettering Cancer Center)

  • Elias ElInati

    (The Francis Crick Institute)

  • Jasmin Zohren

    (The Francis Crick Institute)

  • Takayuki Hirota

    (The Francis Crick Institute)

  • Sarai Pacheco

    (Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Andros Maldonado-Linares

    (Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Marcello Stanzione

    (Faculty of Medicine at the TU Dresden)

  • Obah Ojarikre

    (The Francis Crick Institute)

  • Valdone Maciulyte

    (The Francis Crick Institute)

  • Dirk G. Rooij

    (University of Amsterdam)

  • Attila Tóth

    (Faculty of Medicine at the TU Dresden)

  • Ignasi Roig

    (Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Scott Keeney

    (Memorial Sloan Kettering Cancer Center)

  • James M.A. Turner

    (The Francis Crick Institute)

Abstract

Meiotic cells undergo genetic exchange between homologs through programmed DNA double-strand break (DSB) formation, recombination and synapsis. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes. However, the meiotic functions of the PIKK ATR have remained elusive, because germline-specific depletion of this kinase is challenging. Here we uncover roles for ATR in male mouse prophase I progression. ATR deletion causes chromosome axis fragmentation and germ cell elimination at mid pachynema. This elimination cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germline. ATR is required for synapsis, in a manner genetically dissociable from DSB formation. ATR also regulates loading of recombinases RAD51 and DMC1 to DSBs and recombination focus dynamics on synapsed and asynapsed chromosomes. Our studies reveal ATR as a critical regulator of mouse meiosis.

Suggested Citation

  • Alexander Widger & Shantha K. Mahadevaiah & Julian Lange & Elias ElInati & Jasmin Zohren & Takayuki Hirota & Sarai Pacheco & Andros Maldonado-Linares & Marcello Stanzione & Obah Ojarikre & Valdone Mac, 2018. "ATR is a multifunctional regulator of male mouse meiosis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04850-0
    DOI: 10.1038/s41467-018-04850-0
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    Cited by:

    1. Hironori Abe & Yu-Han Yeh & Yasuhisa Munakata & Kei-Ichiro Ishiguro & Paul R. Andreassen & Satoshi H. Namekawa, 2022. "Active DNA damage response signaling initiates and maintains meiotic sex chromosome inactivation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Adriana K. Alexander & Edward J. Rice & Jelena Lujic & Leah E. Simon & Stephanie Tanis & Gilad Barshad & Lina Zhu & Jyoti Lama & Paula E. Cohen & Charles G. Danko, 2023. "A-MYB and BRDT-dependent RNA Polymerase II pause release orchestrates transcriptional regulation in mammalian meiosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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