Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes.
Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes.
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DOI：
10.7554/elife.10851
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发表时间：
2016-02-04
期刊：
影响因子：
7.7
通讯作者：
Martinez-Perez E
中科院分区：
文献类型：
--
作者：
Crawley O;Barroso C;Testori S;Ferrandiz N;Silva N;Castellano-Pozo M;Jaso-Tamame AL;Martinez-Perez E
WAPL在整个有丝分裂细胞周期中诱导粘附素从DNA解离，调节姐妹染色单体的凝聚力和高阶染色质结构。含有减数分裂特异Kleisin亚基的粘附素复合体控制着减数分裂染色体功能的大部分方面，但WAPL是否调节这些复合体仍不清楚。我们发现，在线虫卵子发生过程中，WAPL-1拮抗含有COH-3/4 kleisins的粘附素的结合，但不拮抗REC-8，表明对WAPL-1的敏感性由kleisin的特性决定。通过限制与染色体相关的COH-3/4粘附素的数量，WAPL-1控制着减数分裂前期的染色体结构。在没有REC-8的情况下，WAPL-1抑制COH-3/4介导的凝聚力，这需要减数分裂重组过程中形成的交叉命运事件。因此，WAPL-1促进了减数分裂粘附素的功能专门化：WAPL-1敏感的COH-3/4复合体调节高阶染色体结构，而WAPL-1不敏感的REC-8复合体提供稳定的凝聚力。令人惊讶的是，在中期I之前，WAPL-1不依赖于粘附素的机制。我们的研究揭示了减数分裂特异的粘附素复合体是如何被调节以确保形成整倍体配子的。DOI：http://dx.doi.org/10.7554/eLife.10851.001大多数动植物细胞的遗传物质都储存在称为染色体的结构中。人体内几乎所有的细胞都含有每条染色体的两份拷贝，一份来自母亲，另一份来自父亲，但性细胞--如卵子和精子--只包含两种染色体的一份。如果卵子或精子含有错误数量的染色体拷贝，就可能发生唐氏综合症等遗传疾病。新的性细胞在一个称为减数分裂的过程中形成，该过程始于一个细胞，该细胞包含每个染色体的两个副本，每个副本复制这些副本。复制的副本被称为姐妹染色单体，由一种名为粘附素的环状蛋白质复合体连接在一起。除了束缚姐妹染色单体，粘附素还影响染色体结构的“高级”组织，并促进其他蛋白质的招募，这些蛋白质对减数分裂过程中染色体行为的不同方面是必不可少的。因此，在减数分裂过程中调节粘附素结合是确保性细胞含有正确数目染色体的关键。在减数分裂结束时，在连续的细胞分裂过程中，粘附素最终分两步从染色体上移除，从而形成含有每条染色体的一个拷贝的性细胞。然而，在减数分裂早期，当染色体经历剧烈的结构变化时，粘附素是否被主动从染色体上移除尚不清楚。使用显微镜和遗传技术相结合的方法研究线虫线虫卵细胞的发育。研究了一种名为WAPL-1的蛋白质在减数分裂早期如何影响粘附素与染色体的结合。这揭示了WAPL-1的S效应依赖于粘连蛋白复合体的特定亚基的同一性。如果这个亚基是一种叫做COH-3或COH-4的蛋白质，那么在减数分裂的早期阶段，WAPL-1会降低粘附素与染色体结合的能力。然而，WAPL-1不影响以称为REC-8的蛋白质为该亚基的粘附素复合体。通过防止COH-3和COH-4粘附素的过度结合，WAPL-1在减数分裂早期调节染色体结构和姐妹染色单体凝聚力。Crawley等人。进一步观察到，在第一次减数分裂之前的阶段，粘附素通过一种不涉及WAPL-1的机制从染色体上移除。下一个挑战是找出为什么含有REC-8蛋白的粘附素被WAPL-1保护而不被释放。这种保护的缺陷是否会引发姐妹染色单体的过早分离也是一个需要回答的重要问题。DOI：http://dx.doi.org/10.7554/eLife.10851.002
Wapl induces cohesin dissociation from DNA throughout the mitotic cell cycle, modulating sister chromatid cohesion and higher-order chromatin structure. Cohesin complexes containing meiosis-specific kleisin subunits govern most aspects of meiotic chromosome function, but whether Wapl regulates these complexes remains unknown. We show that during C. elegans oogenesis WAPL-1 antagonizes binding of cohesin containing COH-3/4 kleisins, but not REC-8, demonstrating that sensitivity to WAPL-1 is dictated by kleisin identity. By restricting the amount of chromosome-associated COH-3/4 cohesin, WAPL-1 controls chromosome structure throughout meiotic prophase. In the absence of REC-8, WAPL-1 inhibits COH-3/4-mediated cohesion, which requires crossover-fated events formed during meiotic recombination. Thus, WAPL-1 promotes functional specialization of meiotic cohesin: WAPL-1-sensitive COH-3/4 complexes modulate higher-order chromosome structure, while WAPL-1-refractory REC-8 complexes provide stable cohesion. Surprisingly, a WAPL-1-independent mechanism removes cohesin before metaphase I. Our studies provide insight into how meiosis-specific cohesin complexes are regulated to ensure formation of euploid gametes. DOI: http://dx.doi.org/10.7554/eLife.10851.001 Most of the genetic material of plant and animal cells is stored in structures called chromosomes. Nearly all the cells in the body contain two copies of each chromosome, one inherited from the mother and the other from the father, but sex cells – such as egg and sperm – contain just one copy of each. If eggs or sperm contain the wrong number of copies of a chromosome, genetic disorders such as Down syndrome can occur. New sex cells form in a process called meiosis, which begins with a cell that contains two copies of each chromosome duplicating each of these copies. The duplicated copies are known as sister chromatids, and are held together by a ring-like protein complex called cohesin. In addition to tethering sister chromatids, cohesin affects the ‘higher-order’ organization of chromosome structure and promotes the recruitment of other proteins that are essential for different aspects of chromosome behavior during meiosis. Therefore, regulating cohesin binding during meiosis is key to ensuring that sex cells contain the correct number of chromosomes. Cohesin is ultimately removed from chromosomes in two steps during the consecutive cell divisions at the end of meiosis, resulting in the formation of sex cells containing a single copy of each chromosome. However, whether cohesin is actively removed from chromosomes during early meiosis, when chromosomes undergo dramatic structural changes, is not known. Using a combination of microscopy and genetic techniques to study the developing egg cells of the worm Caenorhabditis elegans, Crawley et al. investigated how a protein called WAPL-1 affects cohesin binding to chromosomes during early meiosis. This revealed that WAPL-1’s effects depend on the identity of a particular subunit of the cohesin complex. If this subunit is a protein called COH-3 or COH-4, WAPL-1 reduces the ability of cohesin to bind to chromosomes during the early stages of meiosis. However, WAPL-1 does not affect cohesin complexes that instead feature a protein called REC-8 as this subunit. By preventing excessive binding of COH-3 and COH-4 cohesin, WAPL-1 regulates chromosome structure and sister chromatid cohesion during early meiosis. Crawley et al. further observed that during the stage preceding the first meiotic division, cohesin is removed from chromosomes by a mechanism that does not involve WAPL-1. The next challenge is to work out why cohesin containing the REC-8 protein is protected from being released by WAPL-1. Whether defects in this protection can trigger the premature separation of sister chromatids is also an important question to answer. DOI: http://dx.doi.org/10.7554/eLife.10851.002