ATR is required to complete meiotic recombination in mice

• Published in: Nature communications Vol. 9; no. 1; pp. 2622 - 14
• Main Authors: Pacheco, Sarai, Maldonado-Linares, Andros, Marcet-Ortega, Marina, Rojas, Cristina, Martínez-Marchal, Ana, Fuentes-Lazaro, Judit, Lange, Julian, Jasin, Maria, Keeney, Scott, Fernández-Capetillo, Oscar, Garcia-Caldés, Montserrat, Roig, Ignasi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 13/51; 14/32; 14/63; 38/1; 38/39; 38/77; 631/136/2434/1822; 631/80/641/1633; 631/80/641/2187; 64/60; 82/80; Animals; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Checkpoint Kinase 1 - genetics; Checkpoint Kinase 1 - metabolism; CHK1 protein; Chromosome Pairing - genetics; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; Gametes; Genetic recombination; Homologous Recombination; Homology; Humanities and Social Sciences; In Situ Hybridization, Fluorescence; Kinases; Male; Mammals; Meiosis; Meiosis - genetics; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Molecular chains; multidisciplinary; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pharmacology; Prophase; Protein kinase; Proteins; Quality control; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; Recombination; Science; Science (multidisciplinary); Spermatocytes; Spermatocytes - metabolism; Testis - cytology; Testis - metabolism; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04851-z

Precise execution of recombination during meiosis is essential for forming chromosomally-balanced gametes. Meiotic recombination initiates with the formation and resection of DNA double-strand breaks (DSBs). Cellular responses to meiotic DSBs are critical for efficient repair and quality control, but molecular features of these remain poorly understood, particularly in mammals. Here we report that the DNA damage response protein kinase ATR is crucial for meiotic recombination and completion of meiotic prophase in mice. Using a hypomorphic Atr mutation and pharmacological inhibition of ATR in vivo and in cultured spermatocytes, we show that ATR, through its effector kinase CHK1, promotes efficient RAD51 and DMC1 assembly at RPA-coated resected DSB sites and establishment of interhomolog connections during meiosis. Furthermore, our findings suggest that ATR promotes local accumulation of recombination markers on unsynapsed axes during meiotic prophase to favor homologous chromosome synapsis. These data reveal that ATR plays multiple roles in mammalian meiotic recombination. ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a hypomorphic Atr mutation and chemical inhibition, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.