Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair.
Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair.
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DOI：
10.1371/journal.pgen.1000852
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发表时间：
2010-02-19
期刊：
影响因子：
4.5
通讯作者：
Hieter P
中科院分区：
文献类型：
--
作者：
Ben-Aroya S;Agmon N;Yuen K;Kwok T;McManus K;Kupiec M;Hieter P
为了扩大维持基因组稳定性的已知基因谱，我们筛选了最近发布的一组温度敏感型(Ts)酵母突变株，以确定染色体不稳定(CIN)表型。蛋白酶体亚单位基因代表了一个主要的功能群，随后的分析表明在CIN中具有进化上保守的作用。对单个蛋白酶体核心和LID亚基突变的分析表明，半允许温度下的CIN表型与亚基定位到细胞核的失败有关。由此产生的蛋白酶体功能障碍通过损害双链断裂(DSB)修复的动力学来影响染色体的稳定性。我们发现DNA修复蛋白Mms22是DSB修复所必需的，并在DNA损伤后以泛素依赖的方式招募到染色质中。此外，随后蛋白酶体介导的MMS22的降解是细胞周期通过DNA损伤诱导的G2/M期停滞的必要条件和充分条件。我们的结果首次证明了双链断裂修复蛋白是蛋白酶体的靶标，从而将核蛋白酶体活性与DSB修复联系起来。染色体不稳定(CIN)是一种涉及染色体数目或结构改变的基因组表型，是大多数恶性肿瘤的原因。在这篇文章中，我们描述了一种筛选，以确定一组新的CIN基因，并发现蛋白酶体亚基代表一个主要的功能群。我们发现蛋白酶体功能障碍通过损害DNA双链断裂(DSB)修复来影响CIN。以前的研究推测，蛋白酶体需要降解DSB修复机制的一个或多个组件；然而，到目前为止，还没有确定这样的靶点。在这里，我们确定了之前描述的CIN基因MMS22作为蛋白酶体的靶标。我们发现，由于DNA损伤，Mms22被泛素化并招募到染色质中。然后，MMS22经历多泛素化和随后的蛋白酶体介导的降解。我们还提供了证据表明，MMS22的降解对于正常的DNA修复过程和退出DNA损伤引起的G2/M期停滞是重要的。我们的结果首次证明了DSB修复蛋白是一个蛋白酶体靶标，将核蛋白酶体活性与DSB修复联系起来。MMS22的调控机制可以作为一种范式来理解这些额外的蛋白质是如何被蛋白酶体调控的。
To expand the known spectrum of genes that maintain genome stability, we screened a recently released collection of temperature sensitive (Ts) yeast mutants for a chromosome instability (CIN) phenotype. Proteasome subunit genes represented a major functional group, and subsequent analysis demonstrated an evolutionarily conserved role in CIN. Analysis of individual proteasome core and lid subunit mutations showed that the CIN phenotype at semi-permissive temperature is associated with failure of subunit localization to the nucleus. The resultant proteasome dysfunction affects chromosome stability by impairing the kinetics of double strand break (DSB) repair. We show that the DNA repair protein Mms22 is required for DSB repair, and recruited to chromatin in a ubiquitin-dependent manner as a result of DNA damage. Moreover, subsequent proteasome-mediated degradation of Mms22 is necessary and sufficient for cell cycle progression through the G2/M arrest induced by DNA damage. Our results demonstrate for the first time that a double strand break repair protein is a proteasome target, and thus link nuclear proteasomal activity and DSB repair. Chromosome Instability (CIN) is a genome phenotype that involves changes in chromosome number or structure, and accounts for most malignancies. In this paper, we describe a screen to identify a set of novel CIN genes and find that proteasomal subunits represent a major functional group. We show that proteasome dysfunction affects CIN by impairing DNA double strand break (DSB) repair. Previous studies speculated that the proteasome is required to degrade one or more components of the DSB repair machinery; however, until now, no such target has been identified. Here we identify the previously described CIN gene MMS22 as a proteasomal target. We found that, as a result of DNA damage, Mms22 is ubiquitinated and recruited to chromatin. Mms22 then undergoes polyubiquitination and subsequent proteasome-mediated degradation. We also provide evidence that the degradation of Mms22 is important for the normal course of DNA repair and for exit from the G2/M arrest induced by DNA damage. Our results demonstrate for the first time that a DSB repair protein is a proteasome target, linking nuclear proteasomal activity and DSB repair. The mechanism of regulation of Mms22 may serve as a paradigm to understand how these additional proteins are regulated by the proteasome.
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影响因子：
5.3
作者：
Aylon, Y;Liefshitz, B;Kupiec, M
通讯作者：
Kupiec, M
影响因子：
56.9
作者：
Han, Junhong;Zhou, Hui;Zhang, Zhiguo
通讯作者：
Zhang, Zhiguo
DOI：
10.1073/pnas.152264899
发表时间：
2002-08-06
影响因子：
11.1
作者：
Hanway, D;Chin, JK;Romesberg, FE
通讯作者：
Romesberg, FE
影响因子：
64.8
作者：
Collins, Sean R.;Miller, Kyle M.;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
影响因子：
5.3
作者：
Jelinsky, SA;Estep, P;Samson, LD
通讯作者：
Samson, LD