Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
UMC Utrecht, Oncode Institute, Utrecht University, Utrecht, The Netherlands.
Nature. 2020 Jun;582(7812):426-431. doi: 10.1038/s41586-020-2327-4. Epub 2020 May 27.
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. 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.
性染色体在大多数真兽类哺乳动物的雄性中仅共享一小段同源区域，即假常染色体区（PAR），其中双链断裂（DSB）的形成、配对和交叉必须发生，以实现正确的减数分裂分离。细胞如何确保重组发生在 PAR 中尚不清楚。在这里，我们呈现了 PAR 的动态超微结构，并确定了控制顺式和反式作用因子的，这些因子使 PAR 成为雄性小鼠基因组中双链断裂形成最活跃的区域。在断裂形成之前，多个促进双链断裂的因素在 PAR 中过度积累，其染色体轴伸长，姐妹染色单体分离。这些过程与异染色质 mo-2 微卫星阵列有关，需要 MEI4 和 ANKRD31 蛋白，但不需要轴组件 REC8 或 HORMAD1。我们提出，PAR 的重复 DNA 序列赋予其独特的染色质和高级结构，这对重组至关重要。染色体联会触发伸长的 PAR 结构的崩溃，值得注意的是，通过延迟或防止联会，卵母细胞可以被重新编程以在 PAR 中表现出类似于精母细胞的双链断裂水平。因此，PAR 的性别二态性行为部分是由于 PAR 结构成熟、双链断裂形成以及配对和联会完成之间的性别间动力学差异所致。我们的研究结果为减数分裂中性染色体重组建立了一个机制范例。
