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SUPERVISOR(S)

Prof. Christopher Schofield

PROJECT DETAIL

All cancer cells experience greatly increased stress and damage to their genomes relative to non-malignant cells. Consequently, tumours are reliant on the numerous DNA repair pathways for their propagation. Many tumours, therefore, will be sensitive to inhibition of one or more of the many pathways that maintain genome stability. A recent example of a licensed anti-cancer drugs that takes advantage of this principle are PARP inhibitors, that inhibit DNA repair pathways required for the survival of BRCA-defective tumour cells. The interaction between such drugs and tumour defects is called synthetic lethality

We have recently identified a new synthetic lethal interaction involving specific metabolic changes that make many tumours highly dependent upon a specific DNA repair pathway that is active during DNA replication. In this project, we will aim to understand the molecular and cellular basis of this synthetic lethal interaction and work with collaborators in the Department of Chemistry to develop agents that inhibit the DNA repair factors involved. We can then test the proof-of-principle of this synthetic interaction as a first step to developing a new cancer therapy.

Training opportunities:

The group combines a broad range of approaches from structural biology (including cryo-EM), biochemical analysis and pathway reconstitution through to cancer cell biology and cellular genetics. We have a long history of collaborating with chemistry groups to develop new agents that target DNA repair pathways and have strong links with industry that will enable us to take these forward towards the clinic.

Recent publications:

  1. van Wietmarschen N et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 2020; 586(7828):292-298.
  2. McHugh PJ. XPF-ERCC1: Linchpin of DNA crosslink repair. PLoS Genetics 2020 9;16(4):e1008616
  3. Lee SY et al.  Cephalosporins inhibit human metallo-β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo. Chemical Communications 2016 10;52(40):6727-30