REC114 Partner ANKRD31 Controls Number, Timing, and Location of Meiotic DNA Breaks
REC114 Partner ANKRD31 Controls Number, Timing, and Location of Meiotic DNA Breaks
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DOI：
10.1016/j.molcel.2019.03.023
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发表时间：
2019-06-06
期刊：
影响因子：
16
通讯作者：
Keeney, Scott
中科院分区：
文献类型：
--
作者：
Boekhout, Michiel;Karasu, Mehmet E.;Keeney, Scott
双链断裂（DSB）启动同源重组，这对减数分裂染色体配对和分离至关重要。在这里，我们揭示了小鼠ANKRD 31作为DSB形成的多个方面的关键。缺乏ANKRD 31的精母细胞改变了DSB的位置，并且不能将DSB靶向性染色体的假常染色体区域（PAR）。它们也有延迟和/或更少的重组位点，但矛盾的是，更多的DSB，表明DSB失调。未修复的DSB和配对失败-在常染色体上随机，在X和Y上几乎绝对-导致减数分裂停滞和雄性不育。Ankrd 31缺陷的雌性具有减少的卵母细胞储备。晶体结构定义了REC 114中的普列克底物蛋白同源（PH）结构域及其与ANKRD 31的直接分子间接触。在体内，ANKRD 31稳定REC 114与PAR和其他部位的结合。我们的研究结果为ANKRD 31作为一种支架将REC 114和其他因子锚定在特定基因组位置，从而调节DSB形成的模型提供了信息。
Double-strand breaks (DSBs) initiate the homologous recombination that is crucial for meiotic chromosome pairing and segregation. Here, we unveil mouse ANKRD31 as a lynchpin governing multiple aspects of DSB formation. Spermatocytes lacking ANKRD31 have altered DSB locations and fail to target DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. They also have delayed and/or fewer recombination sites but, paradoxically, more DSBs, suggesting DSB dysregulation. Unrepaired DSBs and pairing failures-stochastic on autosomes, nearly absolute on X and Y-cause meiotic arrest and sterility in males. Ankrd31-deficient females have reduced oocyte reserves. A crystal structure defines a pleckstrin homology (PH) domain in REC114 and its direct intermolecular contacts with ANKRD31. In vivo, ANKRD31 stabilizes REC114 association with the PAR and elsewhere. Our findings inform a model in which ANKRD31 is a scaffold anchoring REC114 and other factors to specific genomic locations, thereby regulating DSB formation.