TY - JOUR
T1 - ATR is a multifunctional regulator of male mouse meiosis
AU - Widger, Alexander
AU - Mahadevaiah, Shantha K.
AU - Lange, Julian
AU - Elinati, Elias
AU - Zohren, Jasmin
AU - Hirota, Takayuki
AU - Pacheco, Sarai
AU - Maldonado-Linares, Andros
AU - Stanzione, Marcello
AU - Ojarikre, Obah
AU - Maciulyte, Valdone
AU - De Rooij, Dirk G.
AU - Tóth, Attila
AU - Roig, Ignasi
AU - Keeney, Scott
AU - Turner, James M.A.
N1 - Funding Information:
We are grateful to Bill Earnshaw for providing the CREST anti-centromere antibody, Howard Cooke, Ian Adams for providing the SYCE2 antibody, Paula Cohen for providing the anti-MLH3 antibody, Neil Hunter for the anti-RNF212 antibody, Eric Brown for providing the Atr flox and null mice, members of the Turner laboratory for critical reading of the manuscript and the Francis Crick Institute Technology platforms for excellent assistance. This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001193), the UK Medical Research Council (FC001193) and the Wellcome Trust (FC001193). Work in the Keeney lab is supported in part by the US National Institutes of Health grant R35 GM118092; J.L. was supported in part by American Cancer Society fellowship PF-12-157-01-DMC. S.P., A.M.-L. and I.R. are supported by the Ministerio de Ciencia e Innovación (BFU2016-80370-P).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049730482&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04850-0
DO - 10.1038/s41467-018-04850-0
M3 - Article
C2 - 29976923
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2621
ER -