Characterisation of DNA-protein crosslink proteolysis repair
DNA-protein crosslinks (DPCs) are under-investigated DNA lesions caused by the covalent attachment of proteins to DNA. DPCs are induced by endogenous aldehydes or chemotherapeutic drugs. However, little is known about DPC repair and how cells acquire resistance to DPC-induced chemotherapy. We recently discovered that SPRTN metalloprotease is a specialised and essential enzyme for DNA-protein crosslink repair (Lessel et al. Nature Genetics 2014, Vaz et al. Molecular Cell, 2016).
Link to Cancer: The enzymes involved in DNA repair are promising druggable targets for cancer therapy. Our discovery of SPRTN metalloprotease as the essential component of DNA-protein crosslink repair pathway has been recognised as a promising druggable target for cancer therapy by the European Institute for Innovation and Technology. In addition, we have recently established a partnership with EVOTEC company to develop a first-in-class SPRTN inhibitor for cancer therapy.
This DPhil project aims to characterise SPRTN enzymatic activity and DNA-protein crosslink repair pathway by using standard biochemical and cell biological techniques coupled to the state of the art technologies such as Crisper/Cas9 gene editing, mass-spectrometry and super-resolution microscopy. The student's work will directly help us to elucidate the mechanism of SPRTN in genome stability and its enormous potential for cancer therapy.