Characterisation of DNA-protein crosslink proteolysis repair in cancer and therapy
Nominating Supervisor: Prof Kristijan Ramadan
Second Supervisor: Prof Benedikt Kessler
DNA-protein crosslinks (DPCs) are under-investigated DNA lesions caused by the covalent attachment of proteins to DNA. DPCs are induced by endogenous aldehydes, chemotherapeutic drugs and ionising radiation in hypoxic cells. However, little is known about DPC repair and how do cells acquire resistance to DPC-induced chemo- or radiotherapy. 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). Moreover, we have just found that SPRTN protease in essential for the activation of checkpoint kinase 1 (CHK1), the main replicative checkpoint cascade and a pharmacological target for cancer therapy (Halder et al., Nature Commun. 2019).
Link to Cancer: The enzymes involved in DNA repair are promising druggable targets for cancer therapy. Our discovery of SPRTN metalloprotease and CHK1 as the essential components of DNA-protein crosslink repair pathway have been recognised as the promising druggable targets for cancer therapy by the European Institute for Innovation and Technology.
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. Your work will directly help us to elucidate the mechanism of DNA protein crosslink proteolysis in genome stability and its link to cancer genesis and therapy. We also have access to patient materials and mouse models.
We have a dynamic and vibrant environment in the lab, which currently trains 4 DPhil students and 4 post-doctoral researchers. Our DPhil students are motivated and very happy in our lab. All our students become recognised scientists and secure positions in prestigious universities or pharma companies worldwide. Please check our websites for further details or contact Prof Ramadan directly. Follow us on tweeter: https://twitter.com/Kramadan2
Swagata Halder, Ignacio Torrecilla, Martin D. Burkhalter, Marta Popovic, John Fielden, Bruno Vaz, Judith Oehler, Domenic Pilger, Davor Lessel, Katherine Wiseman, Abhay Narayan Singh, Iolanda Vendrell, Roman Fischer, Melanie Philipp and Kristijan Ramadan*. SPRTN protease and CHK1 kinase Cross-Activation loop Safeguards DNA replication. Nature Communications, 2019, 10; 3142 https://doi.org/10.1038/s41467-019-11095-y. (*corresponding author).
Vaz B, Popovic M, Newman JA, Fielden J, Aitkenhead H, Halder S, Singh AN, Vendrell I, Fischer R, Torrecilla I, Drobnitzky N, Freire R, Amor DJ, Lockhart PJ, Kessler BM, McKenna GW, Gileadi O, Ramadan K*. Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular Cell. 2016 Nov 17;64(4):704-719. doi: 10.1016/j.molcel.2016.09.032 (cited 31 times), (*corresponding author).
Davor Lessel, Bruno Vaz, Swagata Halder… and Janos Terzic*, David J. Amor*, Ivan Dikic*, Kristijan Ramadan*, Christian Kubisch*. Mutations in DVC1/SPRTN cause a syndrome with early-onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genetics. 2014 Nov;46(11):1239-44. (*corresponding authors).