MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner
MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner
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MDM2 介导的 WRN 降解以不依赖于 p53 的方式促进细胞衰老
DOI：
10.1038/s41388-018-0605-5
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发表时间：
2019-04-04
期刊：
影响因子：
8
通讯作者：
Luo, Jianyuan
中科院分区：
文献类型：
--
作者：
Liu, Boya;Yi, Jingjie;Luo, Jianyuan
MDM2（鼠双分钟 2）是 p53 介导的肿瘤抑制功能（包括细胞衰老）的关键阻遏蛋白。我们发现MDM2可以通过调节WRN稳定性来促进细胞衰老。沃纳综合征（WS）是由WRN基因突变引起的，是一种常染色体隐性遗传疾病，其特征是过早衰老。 WRN 功能的丧失会导致人类癌细胞的细胞衰老。在这里，我们发现 MDM2 充当 WRN 蛋白的 E3 连接酶。 MDM2 在体内和体外均与 WRN 相互作用。 MDM2 诱导 WRN 泛素化并显着下调人类细胞中 WRN 蛋白的水平。在DNA损伤反应过程中，WRN易位至核质以促进其DNA修复功能；然而，它会被 MDM2 介导的泛素化途径降解。此外，DNA损伤试剂（例如依托泊苷）诱导的衰老表型至少部分是由MDM2依赖性WRN降解介导的，因为WRN的异位表达可以显着减弱它。这些结果表明，MDM2 通过泛素依赖性降解关键参与调节 WRN 功能，并揭示了 MDM2 通过不依赖 p53 的方式促进细胞衰老的意想不到的作用。
MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.