The WD40-repeat protein-containing deubiquitinase complex: catalysis, regulation, and potential for therapeutic intervention.
The WD40-repeat protein-containing deubiquitinase complex: catalysis, regulation, and potential for therapeutic intervention.
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DOI：
10.1007/s12013-013-9637-1
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发表时间：
2013-09
影响因子：
2.6
通讯作者：
Zhuang, Zhihao
中科院分区：
文献类型：
--
作者：
Villamil, Mark A.;Liang, Qin;Zhuang, Zhihao
泛素化已成为真核生物中一种重要的信号传导机制。去泛素酶（DUBs）抵消泛素化机制的活动，并在细胞泛素化提供另一个水平的控制。毫不奇怪，dub受到严格的监管。除了DUB序列中存在的非催化结构域的调控外，DUB相互作用蛋白越来越多地被认为是DUB活性和功能的重要调节因子。本文综述了与WD40-repeat蛋白相关的dub。许多人类泛素特异性蛋白酶（USPs）被发现与WD40-repeat蛋白相互作用，但这种相互作用如何调节USPs的活性和功能尚不清楚。近年来，在了解包含USP1和USP1相关因子1 （UAF1）的含有WD40-repeat蛋白的DUB复合物的原型方面取得了重大进展。研究表明，UAF1通过潜在的活性位点调节激活USP1， USP1和UAF1之间的复合物形成受丝氨酸磷酸化调节。最近，人类USPs已被认为是一个有希望的抑制剂发现靶标类。针对几种人类USPs的小分子抑制剂已被报道。USP1参与两种主要的DNA损伤反应途径，DNA翻译合成和Fanconi贫血途径。抑制USP1/UAF1去泛素酶复合物代表了一种新的策略，可以增强癌细胞对DNA交联剂的能力，并克服困扰临床癌症化疗的耐药性。本文将讨论USP抑制剂和含WD40-repeat蛋白的USP复合物的研究进展。
Ubiquitination has emerged as an essential signaling mechanism in eukaryotes. Deubiquitinases (DUBs) counteract the activities of the ubiquitination machinery and provide another level of control in cellular ubiquitination. Not surprisingly, DUBs are subjected to stringent regulations. Besides regulation by the noncatalytic domains present in the DUB sequences, DUB-interacting proteins are increasingly realized as essential regulators for DUB activity and function. This review focuses on DUBs that are associated with WD40-repeat proteins. Many human ubiquitin-specific proteases (USPs) were found to interact with WD40-repeat proteins, but little is known as to how this interaction regulates the activity and function of USPs. In recent years, significant progress has been made in understanding a prototypical WD40-repeat protein-containing DUB complex that comprises USP1 and USP1-associated factor 1 (UAF1). It has been shown that UAF1 activates USP1 through a potential active-site modulation, and the complex formation between USP1 and UAF1 is regulated by serine phosphorylation. Recently, human USPs have been recognized as a promising target class for inhibitor discovery. Small molecule inhibitors targeting several human USPs have been reported. USP1 is involved in two major DNA damage response pathways, DNA translesion synthesis and the Fanconi anemia pathway. Inhibiting the USP1/UAF1 deubiquitinase complex represents a new strategy to potentiate cancer cells to DNA- crosslinking agents and to overcome resistance that has plagued clinical cancer chemotherapy. The progress in inhibitor discovery against USPs and the WD40-repeat protein-containing USP complex will be discussed.
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