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

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.