PhD Studentship in the Molecular Basis of Transcription-coupled DNA Repair

Project Description:

How some important forms of DNA damage are repaired in non-dividing cells remains poorly understood. This includes DNA interstrand crosslinks (ICLs) -- a highly toxic form of damage produced spontaneously in our cells, but also by several important anticancer drugs. ICLs sustained through endogenous DNA damage in non-dividing cells must be repaired accurately; failure to accurately repair such damage causes genomic changes precipitating malignant transformation, loss of cell function/viability and ageing. Moreover, it is now widely accepted that tumours contain subset(s) of cells that play a key role in populating the highly proliferative tumour mass, acting in a stem cell-like capacity. Such cells are more resistant to ICL-inducing chemotherapeutics than the bulk tumour population, can persist even after all detectable disease is apparently eradicated, and their persistence is a likely cause of relapse. Targeting this subpopulation of cells warrants significant attention; from both cancer cause/prevention and treatment perspectives understanding ICL repair in non-dividing cells is a pressing issue. We have recently discovered that in non-dividing cells, all lCL repair is transcription-coupled (TC), a process termed TC-ICL repair. Here, we will elucidate the molecular basis of this poorly understood repair pathway. While we have already identified several of the key factors required for TC-ICL repair, we will undertake a genetic (CRISPR) screen for novel candidate TC-ICL repair factors using a recently developed a functional assay. Using genomics methods we will validate the factors discovered in the screen and employ multiple cell biology techniques to obtain a complete picture of TC-ICL repair biology. This will be complemented with biochemical studies, reconstituting and structurally characterising TC-ICL repair. We have programmes to discover inhibitors of several of the known TC-ICL repair factors and the student will help to iteratively improve these. Together, we aim for a complete molecular characterisation of the ICL-TCR repair reaction.

Training Opportunities:

We combine cell biology (including advanced light microscopy), cellular genetics (including genome editing) and biochemistry (including cryo-electron microscopy) to provide a detailed understanding of key DNA repair pathways that are targets for cancer prevention and treatment.

Relevant Publications: Shen, S., Vagner, S. and Robert, C., 2020. Persistent cancer cells: the deadly survivors. Cell, 183(4), pp.860-874.

Funding: competition funded – the successful applicant will be put forward for funding but will be in competition with other students for a small number of studentships. If unsuccessful in obtaining a funded studentship, they will still be able to take up this place on the DPhil Oncology but will need to independently source funding for tuition fees and living expenses.

Entry Requirements and How to Apply: first-class or strong upper second-class undergraduate degree (or predicted) in a biological, medical, mathematical or physical science or international equivalent.

Enquire: Professor Peter McHugh : peter.mchugh@imm.ox.ac.uk

Project Link - Dept Oncology website

General Enquiries: graduate.studies@oncology.ox.ac.uk 

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