Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain; Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, UK.
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain.
Cell Rep. 2019 Jan 15;26(3):775-787.e5. doi: 10.1016/j.celrep.2018.12.074.
Accurate meiotic chromosome segregation critically depends on the formation of inter-homolog crossovers initiated by double-strand breaks (DSBs). Inaccuracies in this process can drive aneuploidy and developmental defects, but how meiotic cells are protected from unscheduled DNA breaks remains unexplored. Here we define a checkpoint response to persistent meiotic DSBs in C. elegans that phosphorylates the synaptonemal complex (SC) to switch repair partner from the homolog to the sister chromatid. A key target of this response is the core SC component SYP-1, which is phosphorylated in response to ionizing radiation (IR) or unrepaired meiotic DSBs. Failure to phosphorylate (syp-1) or dephosphorylate (syp-1) SYP-1 in response to DNA damage results in chromosome non-dysjunction, hyper-sensitivity to IR-induced DSBs, and synthetic lethality with loss of brc-1. Since BRC-1 is required for inter-sister repair, these observations reveal that checkpoint-dependent SYP-1 phosphorylation safeguards the germline against persistent meiotic DSBs by channelling repair to the sister chromatid.
准确的减数分裂染色体分离取决于双链断裂（DSB）引发的同源间交叉的形成。这个过程的不准确性会导致非整倍体和发育缺陷，但减数分裂细胞如何免受非计划的 DNA 断裂仍然未知。在这里，我们定义了秀丽隐杆线虫中持续减数分裂 DSB 引发的检查点反应，该反应使联会复合体（SC）磷酸化，将修复伙伴从同源体切换到姐妹染色单体。该反应的一个关键靶标是核心 SC 成分 SYP-1，它对电离辐射（IR）或未修复的减数分裂 DSB 作出响应而被磷酸化。如果 DNA 损伤时不能对 SYP-1 进行磷酸化（syp-1）或去磷酸化（syp-1），则会导致染色体不分离、对 IR 诱导的 DSBs 过度敏感，并与 brc-1 缺失产生合成致死性。由于 BRC-1 是姐妹间修复所必需的，因此这些观察结果表明，检查点依赖性的 SYP-1 磷酸化通过将修复引导到姐妹染色单体来保护生殖细胞免受持续的减数分裂 DSB 的侵害。
