MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.
MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.
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DOI：
10.1093/g3journal/jkaa065
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发表时间：
2021-04-23
期刊：
影响因子：
--
通讯作者：
Gammie AE
中科院分区：
文献类型：
--
作者：
Arlow T;Kim J;Haye-Bertolozzi JE;Martínez CB;Fay C;Zorensky E;Rose MD;Gammie AE
在真核生物中，DNA错配识别由高度保守的MutSα（Msh 2/Msh 6）和MutSβ（Msh 2/Msh 3）复合物完成。以前，在酿酒酵母中，我们确定删除MSH 6会导致野生型Msh 2水平下降约50%。在这项工作中，我们确定Msh 6稳态水平与Msh 2水平的增加或减少相耦合。虽然Msh 6和Msh 2是受调控的，但Msh 3和Msh 2不是。当Msh 6缺失时，能够与Msh 6相互作用的Msh 2错义变体不稳定;相反，在缺乏Msh 6的细胞中，不能二聚化的变体不会进一步不稳定。在没有Msh 6的情况下，Msh 2以更快的速率被翻转，并且降解由泛素-蛋白酶体途径介导。二聚体界面附近的某些保守赖氨酸的突变恢复了Msh 2的水平，在没有Msh 6的情况下，进一步支持二聚体稳定机制。我们确定了两种可供选择的调节形式，这两种形式都有可能通过赖氨酸残基起作用，包括Gcn 5的乙酰化和Not 4连接酶的泛素化。在没有Gcn 5的情况下，Msh 2水平显著降低;相反，删除Not 4稳定了Msh 2和具有部分功能的Msh 2错义变体。通过Msh 6的存在或Not 4的不存在对Msh 2的稳定作用依赖于Gcn 5。总之，结果表明野生型MutSα错配修复蛋白的稳定性受亚基相互作用、乙酰化和泛素化的控制。
In eukaryotes, DNA mismatch recognition is accomplished by the highly conserved MutSα (Msh2/Msh6) and MutSβ (Msh2/Msh3) complexes. Previously, in the yeast Saccharomyces cerevisiae, we determined that deleting MSH6 caused wild-type Msh2 levels to drop by ∼50%. In this work, we determined that Msh6 steady-state levels are coupled to increasing or decreasing levels of Msh2. Although Msh6 and Msh2 are reciprocally regulated, Msh3 and Msh2 are not. Msh2 missense variants that are able to interact with Msh6 were destabilized when Msh6 was deleted; in contrast, variants that fail to dimerize were not further destabilized in cells lacking Msh6. In the absence of Msh6, Msh2 is turned over at a faster rate and degradation is mediated by the ubiquitin-proteasome pathway. Mutagenesis of certain conserved lysines near the dimer interface restored the levels of Msh2 in the absence of Msh6, further supporting a dimer stabilization mechanism. We identified two alternative forms of regulation both with the potential to act via lysine residues, including acetylation by Gcn5 and ubiquitination by the Not4 ligase. In the absence of Gcn5, Msh2 levels were significantly decreased; in contrast, deleting Not4 stabilized Msh2 and Msh2 missense variants with partial function. The stabilizing effect on Msh2 by either the presence of Msh6 or the absence of Not4 are dependent on Gcn5. Taken together, the results suggest that the wild-type MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.
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DNA不匹配修复和氧化DNA损伤：对癌症生物学和治疗的影响。
影响因子：
5.2
作者：
Bridge G;Rashid S;Martin SA
通讯作者：
Martin SA
DOI：
10.1006/bbrc.1998.9560
发表时间：
1998-10-29
影响因子：
3.1
作者：
Fujimuro, M;Takada, H;Yokosawa, H
通讯作者：
Yokosawa, H
DOI：
10.1073/pnas.1215510110
发表时间：
2013-01-02
影响因子：
11.1
作者：
Arlow, Tim;Scott, Kristan;Gammie, Alison
通讯作者：
Gammie, Alison
影响因子：
9.2
作者：
Habraken, Y;Sung, P;Prakash, S
通讯作者：
Prakash, S
酵母Mutsalpha DNA不匹配修复蛋白MSH2和MSH6的核进口的相互调节。
影响因子：
3.8
作者：
Hayes AP;Sevi LA;Feldt MC;Rose MD;Gammie AE
通讯作者：
Gammie AE