Decoding the non-canonical polyubiquitin chains using chemical approaches

用化学方法破译非正则多泛素链 泛素系统对于调节广泛的细胞和组织功能至关重要。 对人类健康至关重要。尽管我们对泛素系统的了解最初源于 对蛋白酶体介导的蛋白质降解的研究表明，泛素化也是 是许多非蛋白分解功能不可缺少的。许多非正则泛素链与 蛋白质降解以外的细胞功能。K63连接的多泛素链在DNA损伤耐受中的作用 已被发现是真核细胞无错误损伤搭桥的信号。然而，人们对这一点知之甚少 信号调节DNA损伤耐受途径。破译K63的下游蛋白质- 增殖细胞核抗原上的多泛素信号仍有待鉴定。为了破译不同的细胞角色 多泛素化、产生多泛素化蛋白的化学方法和非正则泛素 需要具有定义的结构和长度的链条。这将导致发现下游阅读器 蛋白质在DNA损伤耐受性和其他重要的细胞过程中。它还将使深入的 识别非正则多泛素链的生化和生物物理特征 阅读器蛋白。这将扩大我们对许多生物过程的理解，这些过程由 泛素化，并为治疗干预提供新的途径和靶点。

Decoding the noncanonical polyubiquitin chains using chemical approaches The ubiquitin system is crucial for the regulation of a wide range of cellular and organismal functions essential for the human health. Although our knowledge of the ubiquitin system initially stems from the investigation into proteasome-mediated protein degradation, it has become clear that ubiquitination is also indispensible for many non-proteolytic functions. Many noncanonical ubiquitin chains are associated with cellular functions other than protein degradation. The K63-linked polyubiquitin chain in DNA damage tolerance has been found to be signal for the eukaryotic error-free lesion bypass. However, little is known as to how this signal regulates the DNA damage tolerance pathways. The downstream proteins that decode the K63- polyubiquitin signals on PCNA still need to be identified. In order to decipher the diverse cellular roles of polyubiquitination, chemical approaches of generating polyubiquitinated proteins and noncanonical ubiquitin chains with defined structure and length are needed. This will lead to the discovery of the downstream reader proteins in DNA damage tolerance and other important cellular processes. It will also enable in-depth biochemical and biophysical characterizations of the recognition of noncanonical polyubiquitin chains by the reader proteins. This will broaden our understanding of the many biological processes regulated by ubiquitination and furnish new pathways and targets amenable for therapeutic intervention.