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Characterisation of DNA-protein crosslink proteolysis repair in cancer and therapy


Project Description

THE PROJECT
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.

THE TRAINING
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

PUBLICATIONS
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).

Funding Notes

All complete applications received by 12 noon (UK time) on Friday 11 January 2020 will automatically be considered for all relevant competitive University and funding opportunities, including the Clarendon Fund, Medical Research Council funding, and various College funds. Please refer to the Funding and Costs webpage (View Website) for this course for further details relating to funded scholarships and divisional funding opportunities.

Funded studentships are highly competitive and are awarded to the highest ranked applicant(s) based on the advertised entry requirements for each programme of study.

References

Whilst you must register three referees, the department may start the assessment of your application if two of the three references are submitted by the course deadline and your application is otherwise complete. Please note that you may still be required to ensure your third referee supplies a reference for consideration.

Academic references are strongly encouraged, though you may use up to one professional reference provided that it is relevant to the course.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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