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 de Rooij; Attila Tóth; Ignasi Roig; Scott Keeney; James M A Turner

doi:10.1038/s41467-018-04850-0

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 de Rooij, Attila Tóth, Ignasi Roig, Scott Keeney, James M A Turner

Centre for Stem Cells & Regenerative Medicine

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2621
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04850-0
Publication status	Published - 5 Jul 2018

Keywords

Animals
Ataxia Telangiectasia Mutated Proteins/genetics
Cell Cycle Proteins/genetics
Chromosome Pairing/genetics
Chromosomes, Mammalian/genetics
DNA Breaks, Double-Stranded
In Situ Hybridization, Fluorescence
Male
Meiosis/genetics
Meiotic Prophase I/genetics
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Nuclear Proteins/genetics
Phosphate-Binding Proteins
Rad51 Recombinase/genetics
Spermatocytes/metabolism

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Widger, A., Mahadevaiah, S. K., Lange, J., ElInati, E., Zohren, J., Hirota, T., Pacheco, S., Maldonado-Linares, A., Stanzione, M., Ojarikre, O., Maciulyte, V., de Rooij, D. G., Tóth, A., Roig, I., Keeney, S., & Turner, J. M. A. (2018). ATR is a multifunctional regulator of male mouse meiosis. Nature Communications, 9(1), 2621. https://doi.org/10.1038/s41467-018-04850-0

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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.",

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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

PY - 2018/7/5

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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.

KW - Animals

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - Cell Cycle Proteins/genetics

KW - Chromosome Pairing/genetics

KW - Chromosomes, Mammalian/genetics

KW - DNA Breaks, Double-Stranded

KW - In Situ Hybridization, Fluorescence

KW - Male

KW - Meiosis/genetics

KW - Meiotic Prophase I/genetics

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Nuclear Proteins/genetics

KW - Phosphate-Binding Proteins

KW - Rad51 Recombinase/genetics

KW - Spermatocytes/metabolism

U2 - 10.1038/s41467-018-04850-0

DO - 10.1038/s41467-018-04850-0

M3 - Article

C2 - 29976923

SN - 2041-1723

VL - 9

SP - 2621

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

ATR is a multifunctional regulator of male mouse meiosis

Abstract

Keywords

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