DNA-protein crosslinks (DPCs) are one of the most severe forms of DNA damage. Yet, little is known about mechanisms of repairing DPCs. In this project we focus on the Sprt-type proteases that resolve DPCs to overcome replication stress and faithfully repair the lesions. In humans, SPRTN germline mutations result in Ruijs-Aalfs syndrome, characterised by segmental progeria with early onset of hepatocellular carcinoma. We will investigate how dysregulation of the innate immune system in Sprt-mutated cells contributes to the ageing process and cancer development in the liver. Taken together, this project will provide molecular and genetic insights into the intrinsic molecular mechanisms that resolve DPCs and prevent ageing and cancer.
Role of SPRTN in resolution of DNA protein crosslinks and replication stress