Abstract
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.
Highlights
Precise execution of recombination during meiosis is essential for forming chromosomallybalanced gametes
ATR is activated by the presence of single-stranded DNA, which mainly arises from stalled replication forks or resected double-strand breaks (DSBs). ssDNA is rapidly covered by the ssDNA-binding protein complex RPA, which recruits ATR and its cofactors
We used a previously described hypomorphic mutation that reduces ATR expression in most tissues[14]. This allele mimics a mutation found in some human patients with Seckel syndrome (OMIM 210600), which is characterized by dwarfism, microcephaly, mental retardation, and a beak-like nose[15]
Summary
Precise execution of recombination during meiosis is essential for forming chromosomallybalanced gametes. Our findings suggest that ATR promotes local accumulation of recombination markers on unsynapsed axes during meiotic prophase to favor homologous chromosome synapsis. Correspondence and requests for materials should be addressed to Before the first meiotic division, hundreds of programmed DNA double-strand breaks (DSBs) are formed throughout the genome by the SPO11 protein[1] The repair of these lesions by homologous recombination promotes homologous chromosome synapsis and crossover formation. ATR and its cofactors co-localize with other DNA repair proteins at sites undergoing homologous recombination, suggesting that ATR functions in meiotic recombination[12] This hypothesis has not been formally tested, in part because abolition of Atr expression is embryonically lethal[13]. We overcame this challenge in this study by diminishing ATR function using genetic and pharmacological tools
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