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Shugoshin–MAD2可以不依赖securin而调控分离酶
2020-04-09 11:13

德国拜罗伊特大学Olaf Stemmann研究组最近取得新进展。他们发现检查点诱导的Shugoshin–MAD2可以不依赖securin而调控分离酶。2020年4月8日,《自然》杂志在线发表了这一成果。

研究人员发现人shugoshin 2(SGO2)与纺锤体装配检查点(SAC)激活的MAD2结合后可以抑制分离酶,SGO2是减数分裂cohesin的必要保护因子,其在体细胞中功能未知。SGO2-MAD2可以在功能上替代securin,并且在securin敲除的细胞中可以清除大多数分离酶。Securin和SGO2同时缺失而非这两种蛋白质任意单独缺失会导致分离酶失调,这与未成熟的cohesin切割和细胞毒性有关。与securin相似,SGO2是一种竞争性抑制剂,它使用伪底物序列来阻断分离酶的活性位点。

在体外,APC / C(后期促进复合物,也称为环体)依赖的泛素化和AAA-ATPase TRIP13的激活协同MAD2特异性衔接子p31comet可从SGO2-MAD2中释放分离酶。在缺乏APC / C活性的seccurin基因敲除细胞中,后一种机制一定程度地促进了姐妹染色单体分离。因此,该研究结果揭示了SGO2在有丝分裂中的意外功能,以及不依赖于securin,但受SAC介导的分离酶调控机制。

据悉,SAC在时序上调控真核细胞中姐妹染色单体的分离,并在分离酶切割cohesion-介导的 cohesin时最终引起姐妹染色单体分离。在细胞分裂中期沉默SAC会激活泛素连接酶APC / C,并导致分离酶抑制剂securin的蛋白酶体降解。在缺失securin的情况下,哺乳动物染色体仍按计划分离,但尚不清楚在这种条件下分离酶是如何被调控的。

附:英文原文

Title: Securin-independent regulation of separase by checkpoint-induced shugoshin–MAD2

Author: Susanne Hellmuth, Laura Gmez-H, Alberto M. Pends, Olaf Stemmann

Issue&Volume: 2020-04-08

Abstract: Separation of eukaryotic sister chromatids during the cell cycle is timed by the spindle assembly checkpoint (SAC) and ultimately triggered when separase cleaves cohesion-mediating cohesin1,2,3. Silencing of the SAC during metaphase activates the ubiquitin ligase APC/C (anaphase-promoting complex, also known as the cyclosome) and results in the proteasomal destruction of the separase inhibitor securin1. In the absence of securin, mammalian chromosomes still segregate on schedule, but it is unclear how separase is regulated under these conditions4,5. Here we show that human shugoshin 2 (SGO2), an essential protector of meiotic cohesin with unknown functions in the soma6,7, is turned into a separase inhibitor upon association with SAC-activated MAD2. SGO2–MAD2 can functionally replace securin and sequesters most separase in securin-knockout cells. Acute loss of securin and SGO2, but not of either protein individually, resulted in separase deregulation associated with premature cohesin cleavage and cytotoxicity. Similar to securin8,9, SGO2 is a competitive inhibitor that uses a pseudo-substrate sequence to block the active site of separase. APC/C-dependent ubiquitylation and action of the AAA-ATPase TRIP13 in conjunction with the MAD2-specific adaptor p31comet liberate separase from SGO2–MAD2 in vitro. The latter mechanism facilitates a considerable degree of sister chromatid separation in securin-knockout cells that lack APC/C activity. Thus, our results identify an unexpected function of SGO2 in mitotically dividing cells and a mechanism of separase regulation that is independent of securin but still supervised by the SAC.

DOI: 10.1038/s41586-020-2182-3

Source: https://www.nature.com/articles/s41586-020-2182-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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