The DNA in human cells is regularly damaged, even by the body's normal cellular processes. A DNA break, which is the most severe form of damage, can be caused by environmental exposure to radiation and chemicals but may also result from normal cell metabolism. Left unrepaired, or incorrectly repaired, breaks can cause rearrangements or deletions of regions in our genome that have the potential to cause and drive cancer. Fortunately, life has evolved sophisticated pathways to repair damaged DNA, collectively termed the ‘DNA Damage Response’, and in humans this system is crucial for supressing tumour initiation. However, the DNA damage response is often altered in cancer to help tumours grow or resist chemotherapy and radiation treatment. Our understanding of the DNA damage response has led to the development of breakthrough targeted therapies in patients with cancers that have lost one or more repair pathway. Some cancers suppress the DNA repair system as a strategy to allow cancer cells to divide with profoundly damaged chromosomes. Much less is known about these suppressive systems. Understanding the cellular machinery that subvert the DNA damage response could open new avenues for the development of new treatments for cancer.

Ovarian cancer is the most lethal form of cancer for women. In the UK less than half of women, and only 30% globally, survive more than 5 years after diagnosis. Acquired resistance to front line chemotherapy is a major problem for the treatment of ovarian cancer, and immunotherapy has produced minimal clinical benefit compared to other cancers. There is a clear need for new rationally designed therapies to improve patient outcomes. In ovarian cancer, suppression of the DNA damage response is thought to be the basis for chemotherapy resistance and poorer outcomes for patients. However, we do not fully understand at a molecular level the cellular machinery that is hijacked by ovarian cancers.

In this project the student will employ cutting-edge structural biology approaches (cryo-EM, X-ray crystallography, and AI-driven methods), biochemical reconstitutions, biophysical investigations, and cell biology to uncover how ovarian cancer subvert repair pathways to ignore DNA repair. The lab was recently awarded pump-priming funding from the Sussex Cancer Research Centre (SCRC) to initiate this project in collaboration with the Sussex Drug Discovery Centre and clinical oncologists at the Royal Sussex County Hospital to drive our investigations towards patients.

The project is based in the Genome Damage and Stability Centre (GDSC); a University Centre of Excellence and world-leading research Institute in the field of genome damage and repair. The student will be directly supervised by a research leader at the Genome Centre with strong expertise in DNA repair, structural biology (cryoEM and X-ray crystallography), biochemistry, and biophysics. The student will also benefit from strong interactions within the Genome Centre, especially for cell biology approaches and live cell imaging, the Wolfson Centre of Biological Imaging, and the wider School of Life Sciences. The student will also receive support to attend training workshops and scientific conferences provided by the host lab. The project’s inter-disciplinary approach, combined with the access to state-of-the art facilities and links to the clinic, will offer a unique opportunity to acquire a broad experience in a highly engaging research environment.