The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein.
The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein.
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DOI：
10.1371/journal.pgen.1003216
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Biggins S
中科院分区：
文献类型：
--
作者：
Akiyoshi B;Nelson CR;Duggan N;Ceto S;Ranish JA;Biggins S
着丝点是一种大分子复合物，它组装在着丝粒DNA上，并协调重复染色体的分离。超过60种成分组成了出芽酵母的着丝粒，包括与着丝粒染色质结合的内着丝粒蛋白和直接与微管相互作用的外着丝粒蛋白。然而，对于这些成分如何组装成一个功能性的着丝点，以及是否存在监测着丝点完整性的质量控制机制，人们知之甚少。我们之前开发了一种通过纯化保守的Dsn1着丝粒蛋白来分离着丝粒的方法。我们发现Mub1/Ubr2泛素连接酶复合物通过CENP-CMif2蛋白与着丝点颗粒结合。虽然Mub1/Ubr2在体内不是稳定的着丝粒成分，但它们通过泛素化调节保守的外着丝粒蛋白Dsn1的水平。引人注目的是，Mub1/Ubr2的缺失恢复了突变Dsn1蛋白的水平和活力，这让人想起了针对异常蛋白进行降解的质量控制系统。与此一致的是，当着丝点缺陷时，Mub1/Ubr2有助于维持活力。总之，我们的数据确定了保守的Dsn1着丝点蛋白的一个以前未知的调节机制。我们认为Mub1/Ubr2是监测着丝点完整性的质量控制系统的一部分，从而确保基因组的稳定性。完美的细胞分裂对所有生物的生存至关重要。单条染色体的丢失或获得，这种状态被称为非整倍体，是癌细胞的标志，也是自然流产和遗传性先天缺陷的主要原因。分离是由着丝点介导的，着丝点是一种大分子复合物，它聚集在每条染色体上，并在细胞分裂时附着在纺锤体微管上，将染色体拉到相反的两极。因此，了解着丝点是如何组装和维持的至关重要。在这里，我们发现一个保守的着丝点蛋白的水平是由蛋白水解调节的。我们认为细胞具有质量控制系统，以确保着丝点的完整性和基因组的稳定性。
The kinetochore is the macromolecular complex that assembles onto centromeric DNA and orchestrates the segregation of duplicated chromosomes. More than 60 components make up the budding yeast kinetochore, including inner kinetochore proteins that bind to centromeric chromatin and outer proteins that directly interact with microtubules. However, little is known about how these components assemble into a functional kinetochore and whether there are quality control mechanisms that monitor kinetochore integrity. We previously developed a method to isolate kinetochore particles via purification of the conserved Dsn1 kinetochore protein. We find that the Mub1/Ubr2 ubiquitin ligase complex associates with kinetochore particles through the CENP-CMif2 protein. Although Mub1/Ubr2 are not stable kinetochore components in vivo, they regulate the levels of the conserved outer kinetochore protein Dsn1 via ubiquitylation. Strikingly, a deletion of Mub1/Ubr2 restores the levels and viability of a mutant Dsn1 protein, reminiscent of quality control systems that target aberrant proteins for degradation. Consistent with this, Mub1/Ubr2 help to maintain viability when kinetochores are defective. Together, our data identify a previously unknown regulatory mechanism for the conserved Dsn1 kinetochore protein. We propose that Mub1/Ubr2 are part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability. The flawless execution of cell division is essential to the survival of all organisms. The loss or gain of a single chromosome, the state called aneuploidy, is a hallmark of cancer cells and is the leading cause of spontaneous miscarriages and hereditary birth defects. Segregation is mediated by the kinetochore, the macromolecular complex that assembles on each chromosome and attaches to spindle microtubules to pull chromosomes to opposite poles when cells divide. It is therefore critical to understand how kinetochores are assembled and maintained. Here, we find that the levels of a conserved kinetochore protein are regulated by proteolysis. We propose that cells have quality control systems that ensure kinetochore integrity and thus genome stability.
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影响因子：
5.3
作者：
Gelbart, ME;Rechsteiner, T;Tsukiyama, T
通讯作者：
Tsukiyama, T
影响因子：
64.5
作者：
Black BE;Cleveland DW
通讯作者：
Cleveland DW
DOI：
10.1083/jcb.123.2.387
发表时间：
1993-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brown MT;Goetsch L;Hartwell LH
通讯作者：
Hartwell LH
DOI：
10.1083/jcb.200710019
发表时间：
2008-04-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Emanuele MJ;Lan W;Jwa M;Miller SA;Chan CS;Stukenberg PT
通讯作者：
Stukenberg PT
影响因子：
10.5
作者：
Akiyoshi, Bungo;Nelson, Christian R.;Biggins, Sue
通讯作者：
Biggins, Sue