Defining the role of selected UBLylation pathways in the DNA damage response

泛素样蛋白（UBLs）的翻译后修饰是真核细胞生物学大多数方面的基础。与泛素类似，ubl可以被添加到底物蛋白上，这一过程被称为UBLylation，通过一个酶级联反应，包括ubl激活E1酶、e2偶联酶和E3连接酶。像泛素一样，几个ubl可以作为单个片段或作为不同拓扑链添加到一个或多个底物残基上。最近，一些ubl已被证明通过DNA损伤反应（DDR）促进基因组稳定性。然而，在这方面，人类基因组编码的约15个UBL中的大多数仍未得到充分研究，考虑到UBL和DDR对人类健康的重要性，特别是对健康老龄化的重要性，这令人惊讶：有缺陷的UBL网络以及DNA损伤的积累与各种与年龄相关的疾病，如癌症和神经退行性疾病有关。因此，为了最佳地利用UBL系统用于治疗目的，迫切需要获得新的UBLylation途径的机制见解。为了解决这一限制，该项目旨在揭示DDR中新的UBLylation途径。这项工作将整合可广泛应用的创新方法和技术，如生物物理、结构和最先进的成像方法，以及DNA修复测定和组织培养。此外，该项目涉及一种创新的化学生物学技术，旨在识别UBL级联中常见的瞬时蛋白质-蛋白质相互作用，并对剑桥的阿斯利康进行为期3个月的访问，加入由Josep Forment博士领导的DDR团队之一（另见下面的“CASE奖”部分）。通过确定对DDR重要的新型UBLylation途径，该项目将影响多个细胞生物学领域，从而与“世界级基础生物科学”DTP主题保持一致。从长远来看，这些发现可以帮助设计治疗策略，以治疗和/或预防与错误的UBL网络相关的疾病，从而促进符合当前BBSRC战略重点的健康老龄化。

Posttranslational modification with ubiquitin-like proteins (UBLs) is fundamental to most aspects of eukaryotic cell biology. Similarly to ubiquitin, UBLs can be added to substrate proteins, a process known as UBLylation, through an enzymatic cascade involving a UBL-activating E1 enzyme, an E2-conjugating enzyme and an E3 ligase. Like ubiquitin, several UBLs can be added as a single moiety or as chains of varying topologies to one or several substrate residues. Recently, several UBLs have been shown to promote genome stability through the DNA damage response (DDR). However, most of the ~15 UBLs encoded in the human genome remain understudied in this regard, which is surprising considering the importance of UBLs and the DDR for human health, particularly regarding healthy ageing: defective UBL networks, as well as accumulation of DNA damage, are linked to various age-related diseases, such as cancer and neurodegeneration. Thus, in order to optimally exploit UBL systems for therapeutic purposes, there is a pressing need to gain mechanistic insights into novel UBLylation pathways. To address this limitation, the project aims to unravel novel UBLylation pathways in the DDR. The work will integrate innovative approaches and technologies that can be widely applied, such as biophysical, structural, and state-of-the-art imaging methods, as well as DNA repair assays and tissue culture. Moreover, the project involves an innovative chemical biology technique aimed at identifying transient protein-protein interactions common to UBL cascades, and a 3-month visit to AstraZeneca in Cambridge to join one of their DDR teams led by Dr Josep Forment (see also 'CASE award' section below). By identifying novel UBLylation pathways important for the DDR, the project will impact on multiple cell biology areas, thereby aligning with the 'World class underpinning biosciences' DTP theme. In the longer run, the findings could aid the design of therapeutic strategies to treat and/or prevent diseases linked to faulty UBL networks to promote healthy ageing in line with current BBSRC strategic priorities.