Mapping weak and transient UBL:receptor interactions using tailored photo-crosslinking chemistry

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Post-translational modification (PTM) of proteins is key to virtually all cellular activities. This includes the DNA damage response (DDR), a signalling network critical for facilitating healthy ageing by preventing age-related diseases such as cancer and neurodegenerative pathologies. In particular, PTMs such as ubiquitin-like proteins (UBLs) have recently emerged as critical regulators of a variety of DNA repair pathways1. Elucidating the biochemical consequences of conjugation with UBLs is therefore critical for understanding the functional relevance of these PTM marks. Intense efforts have therefore emerged to identify and characterise the downstream UBL-binding proteins - also called receptors - that interpret and translate UBL marks into precise cellular activities. However, systematic identification of UBL:receptor interactions is challenging due to their mostly weak and transient nature. To address this challenge we aim to integrate a range of chemical biology tools with genetic code expansion to systematically map weak and transient interactions governing UBL networks that have recently emerged as important posttranslational modifiers of the DDR.