ATR is a multifunctional regulator of male mouse meiosis

Alexander Widger, Shantha K. Mahadevaiah, Julian Lange, Elias ElInati, Jasmin Zohren, Takayuki Hirota, Sarai Pacheco, Andros Maldonado-Linares, Marcello Stanzione, Obah Ojarikre, Valdone Maciulyte, Dirk G. Rooij, Attila Tóth, Ignasi Roig, Scott Keeney and James M.A. Turner ()
Additional contact information
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
Andros Maldonado-Linares: 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
Scott Keeney: Memorial Sloan Kettering Cancer Center
James M.A. Turner: The Francis Crick Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04850-0

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