Sex Chromosome Biology Lab, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Molecular Biology Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Nat Commun. 2018 Jul 5;9(1):2621. doi: 10.1038/s41467-018-04850-0.
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.
在减数分裂过程中，同源染色体间通过程序化的 DNA 双链断裂（DSB）形成、重组和联会发生遗传交换。在小鼠中，DNA 损伤调节的磷脂酰肌醇-3-激酶样激酶（PIKK） ATM 调节所有这些过程。然而，PIKK ATR 的减数分裂功能仍然难以捉摸，因为生殖细胞特异性敲除这种激酶具有挑战性。在这里，我们揭示了 ATR 在雄性小鼠减数分裂前期 I 进展中的作用。ATR 缺失导致中期粗线期染色体轴的碎片化和生殖细胞的消除。这种消除不能通过 ATM 和第三个 DNA 损伤调节的 PIKK，PRKDC 的缺失来挽救，这与哺乳动物生殖细胞中存在 PIKK 非依赖性监测机制一致。ATR 对于联会是必需的，其方式在遗传学上与 DSB 形成分离。ATR 还调节 RAD51 和 DMC1 到 DSB 的重组酶加载以及联会和非联会染色体上重组焦点的动态。我们的研究揭示了 ATR 是小鼠减数分裂的关键调节因子。
