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 various endogenous chemicals like aldehydes or by chemotherapeutic drugs. Little is known about how cells repair DPCs and thus acquire resistance to DPC-induced chemotherapy. However, the persistence of DPCs causes genomic instability and cancer. We recently discovered a human syndrome (Ruijs-Aalfs or SPARTAN syndrome) related to the defective DPC repair pathway. SPARTAN syndrome is caused by biallelic and monogenic mutations in SPARTAN gene/protein, and is characterised by genomic instability, premature ageing and liver cancer in children (Lessel et al. Nature Genetics 2014). We demonstrated that SPARTAN is a DNA-dependent metalloprotease, which enzymatically (by its metalloprotease activity) removes covalently attached proteins from DNA (Vaz et al. Molecular Cell, 2016). Altogether, our results demonstrate that we have discovered a novel and specialised DNA repair pathway, namely DNA-protein crosslink proteolysis repair pathway that protects humans from cancer and accelerated ageing (Vaz et al., TIBS, 2017).
This DPhil project aims to delineate this new 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-resolutions microscopy.