Main achievements:
1.) We conducted biochemical screens to reveal the first factors controlling the activity of the SPRTN protease in human cells (Zhao et al., NAR 2021). We revealed that the enzyme USP7 governs a regulatory switch, which controls SPRTN by switching the enzymes preference from inactivating autocleavage to substrate cleavage in times of need.
2.) We revealed how the activity of SPRTN is restricted to crosslinked protein adducts, while leaving surrounding chromatin proteins unharmed. By developing new model substrates, we were able to show that SPRTN achieves specificity by recognizing specific DNA structures, which restricts activation of the enzyme to biologically relevant scenarios (Reinking et al., Mol Cell 2020, Reinking and Stingele, STARProtocols 2021).
3.) We identified helicase-mediated protein unfolding by the FANCJ helicase to be required for replication-coupled DPC repair (Yaneva et al., Mol Cell 2023).
4.) We identified a non-proteolytic release mechanisms for endogenous DPCs formed by the HMCES protein (Donsbach et al., EMBO J 2023).
5.) We successfully developed the proposed new methodology to determine the nature of the protein component of DPCs in various experimental scenarios (Weickert et al., Nat Commun 2023) as well as their genomic position (Carnie et al., Nat Cell Bio 2024). Withs these tools in hand, we have discovered and characterised novel global-genome as well as transcription-coupled DNA repair pathways with imminent relevance for the aetiology of human premature ageing and cancer predisposition syndromes (Weickert et al., Nat Commun 2023, Carnie et al., Nat Cell Bio 2024, Carnie et al., EMBO J 2024).
