Ensuring meiotic DNA break formation in the mouse pseudoautosomal region
Ensuring meiotic DNA break formation in the mouse pseudoautosomal region
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DOI：
10.1038/s41586-020-2327-4
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发表时间：
2020-05-27
期刊：
影响因子：
64.8
通讯作者：
Keeney, Scott
中科院分区：
文献类型：
--
作者：
Acquaviva, Laurent;Boekhout, Michiel;Keeney, Scott
在小鼠中，性染色体的假常染色体区域经历动态结构重排，以促进高比率的DNA双链断裂并确保X-Y重组。大多数真兽目哺乳动物的雄性性染色体仅共享一个小的同源片段，即假常染色体区域（PAR），其中必须发生双链断裂（DSB）的形成、配对和交换以进行正确的减数分裂分离（1，2）。细胞如何确保在PAR中发生重组尚不清楚。在这里，我们提出了一个动态的超微结构的PAR，并确定控制顺式和反式作用的因素，使PAR的最热段DSB形成的雄性小鼠基因组。在断裂形成之前，多种DSB促进因子在PAR中过度积累，其染色体轴伸长，姐妹染色单体分离。这些过程与异色mo-2小卫星阵列有关，需要MEI 4和ANKRD 31蛋白，但不需要轴组件REC 8或HORMAD 1。我们建议，PAR的重复DNA序列赋予独特的染色质和更高阶的结构，是重组的关键。染色体突触触发细长的PAR结构的崩溃，值得注意的是，卵母细胞可以被重新编程，表现出精母细胞样水平的DSB在PAR中简单地通过延迟或阻止突触。因此，PAR的性二态行为部分是由于两性之间的PAR结构的成熟，DSB的形成和完成配对和突触之间的比赛中的动力学差异。我们的发现为减数分裂中性染色体的重组建立了一个机制范例。
In mice, the pseudoautosomal region of the sex chromosomes undergoes a dynamic structural rearrangement to promote a high rate of DNA double-strand breaks and to ensure X-Y recombination.Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation(1,2). How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.