The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor.
The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor.
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E3 泛素连接酶 UBE3A 通过调节 BMAL1 转录因子成为分子生物钟的组成部分
DOI：
10.1093/nar/gku225
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发表时间：
2014-05
影响因子：
14.9
通讯作者：
Meng QJ
中科院分区：
文献类型：
--
作者：
Gossan NC;Zhang F;Guo B;Jin D;Yoshitane H;Yao A;Glossop N;Zhang YQ;Fukada Y;Meng QJ
生物钟蛋白的翻译后修饰（如泛素化）对于维持进化上保守的生物钟的精确性和鲁棒性至关重要。核心时钟转录因子BMAL 1（脑和肌肉Arnt样1）的泛素化最近有报道。然而，目前还不清楚BMAL 1泛素化是否影响昼夜节律起搏和什么泛素连接酶（S）参与。在这里，我们表明，激活UBE 3A（通过表达病毒致癌基因E6/E7）破坏小鼠胚胎成纤维细胞的昼夜节律振荡，使用PER 2：：Luc动力学，内源性信使核糖核酸和BMAL 1蛋白水平的节奏。E6/E7的过表达降低了BMAL 1的水平，增加了其泛素化和蛋白酶体降解。UBE 3A可以通过泛素连接酶依赖的方式结合并降解BMAL 1。这在存在和不存在E6/E7的情况下都发生。我们提供了体外（敲低/过表达在哺乳动物细胞）和体内（遗传操作在果蝇）的内源性作用的UBE 3A在调节昼夜节律的动力学和有节奏的运动行为的证据。总之，我们的数据揭示了UBE 3A在哺乳动物和苍蝇的昼夜节律系统调节中的重要和保守作用，并确定了癌基因E6/E7介导的细胞转化和昼夜节律（BMAL 1）破坏之间的新机制联系。
Post-translational modifications (such as ubiquitination) of clock proteins are critical in maintaining the precision and robustness of the evolutionarily conserved circadian clock. Ubiquitination of the core clock transcription factor BMAL1 (brain and muscle Arnt-like 1) has recently been reported. However, it remains unknown whether BMAL1 ubiquitination affects circadian pacemaking and what ubiquitin ligase(s) is involved. Here, we show that activating UBE3A (by expressing viral oncogenes E6/E7) disrupts circadian oscillations in mouse embryonic fibroblasts, measured using PER2::Luc dynamics, and rhythms in endogenous messenger ribonucleic acid and protein levels of BMAL1. Over-expression of E6/E7 reduced the level of BMAL1, increasing its ubiquitination and proteasomal degradation. UBE3A could bind to and degrade BMAL1 in a ubiquitin ligase-dependent manner. This occurred both in the presence and absence of E6/E7. We provide in vitro (knockdown/over-expression in mammalian cells) and in vivo (genetic manipulation in Drosophila) evidence for an endogenous role of UBE3A in regulating circadian dynamics and rhythmic locomotor behaviour. Together, our data reveal an essential and conserved role of UBE3A in the regulation of the circadian system in mammals and flies and identify a novel mechanistic link between oncogene E6/E7-mediated cell transformation and circadian (BMAL1) disruption.
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影响因子：
15.9
作者：
Mabb, Angela M.;Judson, Matthew C.;Zylka, Mark J.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
影响因子：
--
作者：
Gossan, Nicole;Zeef, Leo;Hensman, James;Hughes, Alun;Bateman, John F.;Rowley, Lynn;Little, Christopher B.;Piggins, Hugh D.;Rattray, Magnus;Boot-Handford, Raymond P.;Meng, Qing-Jun
通讯作者：
Meng, Qing-Jun
影响因子：
12.4
作者：
Louria-Hayon, I.;Alsheich-Bartok, O.;Haupt, Y.
通讯作者：
Haupt, Y.
影响因子：
64.5
作者：
SCHEFFNER, M;HUIBREGTSE, JM;HOWLEY, PM
通讯作者：
HOWLEY, PM
影响因子：
2.7
作者：
Ohsaki, Kanae;Oishi, Katsutaka;Ishida, Norio
通讯作者：
Ishida, Norio