Department of Chemistry and Biochemistry, University of Delaware, 214A Drake Hall, Newark, DE 19716, USA.
Cell Biochem Biophys. 2013 Sep;67(1):111-26. doi: 10.1007/s12013-013-9637-1.
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.
泛素化已成为真核生物中一种重要的信号机制。去泛素化酶 (DUBs) 拮抗泛素化机制的活性，并在细胞泛素化中提供另一层控制。毫不奇怪，DUBs 受到严格的调控。除了 DUB 序列中非催化结构域的调控外，DUB 相互作用蛋白也越来越被认为是 DUB 活性和功能的重要调节因子。本综述重点介绍与 WD40 重复蛋白相关的 DUB。许多人类泛素特异性蛋白酶 (USP) 被发现与 WD40 重复蛋白相互作用，但对于这种相互作用如何调节 USP 的活性和功能知之甚少。近年来，人们在理解包含 USP1 和 USP1 相关因子 1 (UAF1) 的典型 WD40 重复蛋白包含的 DUB 复合物方面取得了重大进展。已经表明，UAF1 通过潜在的活性位点调节来激活 USP1，并且 USP1 和 UAF1 之间的复合物形成受丝氨酸磷酸化调节。最近，人类 USP 已被认为是抑制剂发现的有前途的靶标类别。已经报道了针对几种人类 USP 的小分子抑制剂。USP1 参与两种主要的 DNA 损伤反应途径，DNA 跨损伤合成和范可尼贫血途径。抑制 USP1/UAF1 去泛素化酶复合物代表了一种增强癌细胞对 DNA 交联剂的作用并克服困扰临床癌症化疗的耐药性的新策略。将讨论针对 USP 和包含 WD40 重复蛋白的 USP 复合物的抑制剂发现的进展。
