The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance.
The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance.
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多效性去泛素酶UBP3赋予了非倍性耐受性。
DOI：
10.1101/gad.287474.116
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发表时间：
2016-10-15
影响因子：
10.5
通讯作者：
Amon A
中科院分区：
文献类型：
--
作者：
Dodgson SE;Santaguida S;Kim S;Sheltzer J;Amon A
在这项研究中，道奇森等人。使用全基因组筛查损害非整倍体酵母适合性的基因缺失，并确定去泛素酶Ubp3是非整倍体细胞动态平衡的关键调节因子。他们发现，Ubp3是跨物种保存的非整倍体细胞适合性的守护者。非整倍体--即整个染色体获得或丢失的不平衡核型--会导致细胞和机体水平的适合性降低，但也是人类癌症的一个标志。非整倍体导致多种细胞应激，包括基因组不稳定、蛋白质毒性和氧化应激，以及蛋白质运输障碍。脱泛素酶Ubp3是非整倍体细胞内稳态的关键调节因子，通过全基因组筛查损害非整倍体酵母适合性的基因缺失而被鉴定。我们发现，UBP3的缺失会加剧非整倍体细胞的核型特异性表型和整体应激，包括氧化和蛋白毒性应激。事实上，Ubp3对于整倍体细胞中正常的蛋白酶体功能是必不可少的，而这种去泛素酶的缺失导致了蛋白酶体在非整倍体酵母中进一步的蛋白毒性。值得注意的是，UBP3在非整倍体细胞中的重要性是保守的。人类UBP3同源基因USP10的缺失不利于人类细胞在染色体错误分离时的适合性，这种适合性缺陷伴随着自噬抑制。因此，我们在酵母中使用全基因组筛查来确定跨物种保存的非整倍体细胞适合性的守护者。我们认为，干扰Ubp3/USP10功能可能是开发新的癌症治疗药物的有效途径。
In this study, Dodgson et al. used a genome-wide screen for gene deletions that impair the fitness of aneuploid yeast and identified the deubiquitinase Ubp3 as a key regulator of aneuploid cell homeostasis. They found that Ubp3 is a guardian of aneuploid cell fitness conserved across species. Aneuploidy—or an unbalanced karyotype in which whole chromosomes are gained or lost—causes reduced fitness at both the cellular and organismal levels but is also a hallmark of human cancers. Aneuploidy causes a variety of cellular stresses, including genomic instability, proteotoxic and oxidative stresses, and impaired protein trafficking. The deubiquitinase Ubp3, which was identified by a genome-wide screen for gene deletions that impair the fitness of aneuploid yeast, is a key regulator of aneuploid cell homeostasis. We show that deletion of UBP3 exacerbates both karyotype-specific phenotypes and global stresses of aneuploid cells, including oxidative and proteotoxic stress. Indeed, Ubp3 is essential for proper proteasome function in euploid cells, and deletion of this deubiquitinase leads to further proteasome-mediated proteotoxicity in aneuploid yeast. Notably, the importance of UBP3 in aneuploid cells is conserved. Depletion of the human homolog of UBP3, USP10, is detrimental to the fitness of human cells upon chromosome missegregation, and this fitness defect is accompanied by autophagy inhibition. We thus used a genome-wide screen in yeast to identify a guardian of aneuploid cell fitness conserved across species. We propose that interfering with Ubp3/USP10 function could be a productive avenue in the development of novel cancer therapeutics.
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