Sem1, the yeast ortholog of a human BRCA2-binding protein, is a component of the proteasome regulatory particle that enhances proteasome stability
Sem1, the yeast ortholog of a human BRCA2-binding protein, is a component of the proteasome regulatory particle that enhances proteasome stability
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DOI：
10.1242/jcs.01575
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发表时间：
2004-12-15
影响因子：
4
通讯作者：
Kobayashi, H
中科院分区：
文献类型：
--
作者：
Funakoshi, M;Xi, L;Kobayashi, H
蛋白酶体对多泛素化蛋白的降解通常需要辅助因素；这些包括结合多聚泛素链和蛋白酶体调节颗粒的受体蛋白。此类因子 Dsk2 的过量产生在酿酒酵母中是致命的，我们在这里表明这种致死性可以通过 SEM1 的突变来抑制，SEM1 是一种先前被认为是编码 DSS1 的人类基因的直系同源基因，它与 BRCA2 DNA 修复蛋白结合。酵母 sem1 突变体会积累多聚泛素化蛋白，存在蛋白酶体介导的降解缺陷，并且无法在各种胁迫条件下生长。此外，sem1 因蛋白酶体亚基突变而具有综合致死性。我们证明 Sem1 是蛋白酶体调节颗粒的组成部分，特别是盖子亚复合物。 Sem1 的缺失会损害 26S 蛋白酶体的稳定性，同时删除 RPN10 会大大增强 sem1Delta 缺陷。 Rpn10 蛋白酶体亚基似乎与 Sem1 一起发挥作用，维持调节颗粒的盖子和底座亚复合物的关联。我们的数据表明了这种蛋白质-蛋白质稳定的潜在机制，并且还表明完整的蛋白酶体调节颗粒是对 DNA 损伤做出反应所必需的。
Degradation of polyubiquitinated proteins by the proteasome often requires accessory factors; these include receptor proteins that bind both polyubiquitin chains and the regulatory particle of the proteasome. Overproduction of one such factor, Dsk2, is lethal in Saccharomyces cerevisiae and we show here that this lethality can be suppressed by mutations in SEM1, a gene previously recognized as an ortholog of the human gene encoding DSS1, which binds the BRCA2 DNA repair protein. Yeast sem1 mutants accumulate polyubiquitinated proteins, are defective for proteasome-mediated degradation and cannot grow under various stress conditions. Moreover, sem1 is synthetically lethal with mutations in proteasome subunits. We show that Sem1 is a component of the regulatory particle of the proteasome, specifically the lid subcomplex. Loss of Sem1 impairs the stability of the 26S proteasome and sem1Delta defects are greatly enhanced by simultaneous deletion of RPN10. The Rpn10 proteasome subunit appears to function with Sem1 in maintaining the association of the lid and base subcomplexes of the regulatory particle. Our data suggest a potential mechanism for this protein-protein stabilization and also suggest that an intact proteasomal regulatory particle is required for responses to DNA damage.