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Discovering and developing ways to inhibit the BubR1-PIDD interaction to enhance tumour cell death in response to radiation.

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  • Full or part time
    Dr Ruth Thompson
    Prof J Sayers
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Supervisor(s): Dr Ruth Thompson, Professor Jon Sayers, Dr Victor Bolanos-Garcia (Oxford Brookes University)

Resistance to radiotherapy is a major obstacle in cancer therapy. Often, radiotherapy kills cancer cells and shrinks tumours right down and the patient appears to go into remission but then, the few remaining cancer cells not initially killed by the treatment, grow and divide to form an entirely radiation-resistant tumour and the patient dies. Our previous work has revealed a mechanism by which tumour cells can evade cell death in response to radiation. By working to fully understand this mechanism this project aims to identify and develop drugs to inhibit it and sensitise cancer cells to radiotherapy.

The PIDDosome, is a caspase-activating apoptotic platform. In response to apoptotic signals, PIDD binds the adaptor protein RAIDD and cleaves and activates the effector caspase, caspase-2, leading to cell death. We have shown that in response to radiation, the mitotic spindle checkpoint effector protein BubR1 directly binds to PIDD in mitosis, preventing the interaction with RAIDD and thus inhibiting apoptosis. This project will take a two-pronged approach to characterize this interaction and identify ways to inhibit it, thus promoting cancer cell death in response to radiation.

Aim 1: Characterise the interaction of BubR1-PIDD using structure based site-directed mutagenesis and a variety of spectroscopy and biophysical techniques, protein overexpression of BubR1 fragments and PIDD, 1D NMR and cell biology.
Aim 2: Using FRET screening approach, screen for loss of the PIDD-BubR1 interaction following incubation with a peptide library.

You will join an expanding and enthusiastic group studying exciting novel aspects of the cellular response to DNA damage. This project is spread across a multidisciplinary team consisting of cell biologists, protein biochemists and structural biologists and will be in part carried out in Dr Bolanos-Garcia’s lab in Oxford. The successful candidate will be required to travel to Oxford on two or three occasions and stay for a few months at a time.

Proposed start date: October 2019

Salary/stipend rate: Starting at £15,009 for 4 years

Funding Notes

The Royal Society cover home fees and stipend for four years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.
Salary/stipend rate: Starting at £15,009 for 4 years

Entry Requirements:
Must hold a relevant degree at 2:1 or better and have either a masters degree or relevant work experience. Suited to an outstanding biochemistry graduate with a strong interest in structural biology. Practical experience in molecular and cell biology techniques is desirable. Full training provided in all necessary areas of protein biochemistry and structural work.

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