Phosphoregulation of HORMA domain protein HIM-3 promotes asymmetric synaptonemal complex disassembly in meiotic prophase in Caenorhabditis elegans.
Phosphoregulation of HORMA domain protein HIM-3 promotes asymmetric synaptonemal complex disassembly in meiotic prophase in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1008968
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发表时间：
2020-11
期刊：
影响因子：
4.5
通讯作者：
Carlton PM
中科院分区：
文献类型：
--
作者：
Sato-Carlton A;Nakamura-Tabuchi C;Li X;Boog H;Lehmer MK;Rosenberg SC;Barroso C;Martinez-Perez E;Corbett KD;Carlton PM
在减数分裂的两次细胞分裂中，二倍体基因组通过离散的两步去除染色体凝聚力而减少为互补的单倍体组，这是大多数真核生物通过保护着丝粒处的凝聚力直到第二次分裂来完成的任务。然而，在没有确定的着丝粒的真核生物中，替代策略已经创新。其中最好的理解是在线虫秀丽隐杆线虫中发现的：在单个偏离中心的交叉将染色体分成两个片段或臂后，几个染色体相关蛋白或翻译后修饰被特异性地分配到较短或较长的臂，在那里它们通过未知的机制促进正确的内聚损失时间。在这里，我们调查了减数分裂轴HORMA结构域蛋白HIM-3，并表明它成为磷酸化在其C-末端，在保守的“封闭基序”区域内的相关HORMA结构域蛋白HTP-1和HTP-2的约束。HTP-2的结合在体外试验中通过闭合基序的磷酸化而被废除，强烈表明HIM-3的体内磷酸化可能调节染色体轴的分级结构。HIM-3的磷酸化仅发生在突触染色体上，并且类似于先前描述的联会复合体的其他磷酸化蛋白质，在指定交换位点后变得限于短臂。HIM-3磷酸化状态的调节是联会复合体中心元件从长臂上及时解离所必需的，也是HTP-1和HTP-2从短臂上解离的适当时机所必需的。因此，HIM-3的磷酸化在建立短臂和长臂的身份中起作用，从而有助于两步染色体分离的稳健性。为了在减数分裂中正确分离，复制的染色体之间的凝聚力必须在第一次减数分裂细胞分裂后保持，因此染色体可以保持在一起，直到它们最终在第二次分裂中分离。虽然大多数生物在第一次分裂中使用着丝粒来保护染色体的凝聚力，但线虫C。而缺少单个着丝粒的秀丽线虫，则只在染色体的一段称为“长臂”的区域上保护凝聚力。已知长臂（及其互补物，短臂）积累特定的蛋白质和蛋白质修饰，但不知道短臂和长臂最初是如何区分的，也不知道它们各自的功能是如何实现的。我们在这里报告，染色体轴蛋白HIM-3及其磷酸化修饰对于确保短臂和长臂功能的稳健建立是重要的。我们表明，磷酸化的HIM-3分区的短臂后，交叉重组位点被指定，和HIM-3突变体，模仿组成型磷酸化延迟正常建立的两个互补的臂域。我们的发现揭示了染色体生物学中另一层的调节机制。
In the two cell divisions of meiosis, diploid genomes are reduced into complementary haploid sets through the discrete, two-step removal of chromosome cohesion, a task carried out in most eukaryotes by protecting cohesion at the centromere until the second division. In eukaryotes without defined centromeres, however, alternative strategies have been innovated. The best-understood of these is found in the nematode Caenorhabditis elegans: after the single off-center crossover divides the chromosome into two segments, or arms, several chromosome-associated proteins or post-translational modifications become specifically partitioned to either the shorter or longer arm, where they promote the correct timing of cohesion loss through as-yet unknown mechanisms. Here, we investigate the meiotic axis HORMA-domain protein HIM-3 and show that it becomes phosphorylated at its C-terminus, within the conserved “closure motif” region bound by the related HORMA-domain proteins HTP-1 and HTP-2. Binding of HTP-2 is abrogated by phosphorylation of the closure motif in in vitro assays, strongly suggesting that in vivo phosphorylation of HIM-3 likely modulates the hierarchical structure of the chromosome axis. Phosphorylation of HIM-3 only occurs on synapsed chromosomes, and similarly to other previously-described phosphorylated proteins of the synaptonemal complex, becomes restricted to the short arm after designation of crossover sites. Regulation of HIM-3 phosphorylation status is required for timely disassembly of synaptonemal complex central elements from the long arm, and is also required for proper timing of HTP-1 and HTP-2 dissociation from the short arm. Phosphorylation of HIM-3 thus plays a role in establishing the identity of short and long arms, thereby contributing to the robustness of the two-step chromosome segregation. To segregate properly in meiosis, cohesion between replicated chromosomes must remain after the first meiotic cell division, so chromosomes can be held together until they finally separate in the second division. While the majority of organisms use centromeres to protect chromosome cohesion in the first division, the nematode worm C. elegans, which lacks single centromeres, instead protects cohesion only on a segment of the chromosome known as the “long arm”. The long arm (and its complement, the short arm) are known to accumulate specific proteins and protein modifications, but it is not known how the short and long arms are first distinguished, nor how their separate functions are carried out. We report here that the chromosome axis protein HIM-3 and its modification by phosphorylation is important for ensuring the robust establishment of short and long arm functions. We show that phosphorylated HIM-3 partitions to the short arms after crossover recombination sites are designated, and HIM-3 mutants that mimic constitutive phosphorylation delay the normal establishment of the two complementary arm domains. Our findings reveal another layer of regulation to an outstanding mystery in chromosome biology.
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