hMutSα is protected from ubiquitin-proteasome-dependent degradation by atypical protein kinase Cξ phosphorylation
hMutSα is protected from ubiquitin-proteasome-dependent degradation by atypical protein kinase Cξ phosphorylation
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DOI：
10.1016/j.jmb.2005.02.001
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发表时间：
2005-04-22
影响因子：
5.6
通讯作者：
Lautier, D
中科院分区：
文献类型：
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作者：
Hernandez-Pigeon, H;Quillet-Mary, A;Lautier, D
hMutS alpha（hMSH 2-hMSH 6）蛋白异源二聚体在错配修复（MMR）过程中检测DNA错配中起关键作用。我们最近报道了hMutS α蛋白被泛素-蛋白酶体途径以细胞类型依赖性方式降解，表明一种或几种调节剂可能干扰hMutS α蛋白的泛素化和降解。另一方面，我们和其他人已经表明，蛋白激酶C（PKC）参与作为一个积极的调节MMR活动。在这里，我们提供的证据表明，非典型的PKC zeta调节泛素化，降解和hMutS α蛋白的水平。使用PKC zeta转染的U937和PKC zeta siRNA转染的MRC-5细胞系，我们发现PKC zeta蛋白表达与hMutS α的表达以及与MMR活性相关，但与hMutS α蛋白泛素化和降解呈负相关。有趣的是，PKC zeta与hMSH 2和hMSH 6蛋白相互作用并磷酸化两者。此外，在体外试验中，PK zeta C介导磷酸化事件，通过泛素-蛋白酶体途径降低hMutS α蛋白降解。总之，我们的研究结果表明，PKC ζ调节hMutS α的稳定性和蛋白质水平，并建议PKC ζ在基因组稳定性的作用，通过调节MMR活性。(c)2005爱思唯尔有限公司保留所有权利。
The hMutS alpha (hMSH2-hMSH6) protein heterodimer plays a critical role in the detection of DNA mispairs in the mismatch repair (MMR) process. We recently reported that hMutS alpha proteins were degraded by the ubiquitin-proteasome pathway in a cell-type-dependent manner, indicating that one or several regulator(s) may interfere with hMutS alpha protein ubiquitination and degradation. On the other hand, we and others have shown that protein kinase C (PKC) is involved as a positive regulator of MMR activity. Here, we provide evidence that the atypical PKC zeta regulates ubiquitination, degradation, and levels of hMutS alpha proteins. Using both PKC zeta-transfected U937 and PKC zeta siRNA-transfected MRC-5 cell lines, we found that PKC zeta protein expression was correlated with that of hMutS alpha as well as with MMR activity, but was inversely correlated with hMutS alpha protein ubiquitination and degradation. Interestingly, PKC zeta interacts with hMSH2 and hMSH6 proteins and phosphorylates both. Moreover, in an in vitro assay PK zeta C mediates phosphorylation events decreasing hMutS alpha protein degradation via the ubiquitin-proteasome pathway. Altogether, our results indicate that PKC zeta modulates hMutS alpha stability and protein levels, and suggest a role for PKC zeta in genome stability by regulating MMR activity. (c) 2005 Elsevier Ltd. All rights reserved.