DNA repair fidelity, radiosensitivity and cancer
Nominating Supervisor: Timothy Humphrey
Second Supervisor: Vincenzo D’Angiolella
With almost half of all cancer patients receiving radiotherapy, tumour-specific radiosensitization remains an important goal for cancer research. Radiosensitivity is associated with failure to accurately repair DNA double-strand breaks (DSBs), thus leading to cell death. Using yeast and human model systems we have previously identified a number of genes required for efficient DSB repair, radioresistance and genome stability. Further, we have exploited a conserved synthetic lethal relationship to further target cancers deficient in one such gene, SETD2, which has recently entered clinical trials.
The aim of this project is to identify and characterize genes required for high fidelity DSB repair. Such genes will be examined to determine their role in suppressing mutagenic repair, radiation sensitivity, and immune responses. Findings will be exploited, using synthetic lethal pharmacological approaches, to enhance radiation targeting of specific cancers. Techniques will include cancer genetics, radiation biology, cell and molecular biology and biochemistry.
The DPhil project will provide an opportunity to join cutting-edge research lab addressing important basic research questions with clinical translational potential. The student will undertake an exciting novel project and learn/develop state of the art techniques in a variety of disciplines including mammalian genetics, radiobiology, cell and molecular biology, biochemistry and bioinformatics. Further transferrable skills (eg writing, presentational, organizational) will also be acquired. The Humphrey lab has extensive successful DPhil supervision experience, with students going on to successful careers in research, medicine and industry.
Pai, C-C., Deegan, R.S., Gal, C., Subramanian, L., Sarkar,S., Blaikley, E.J., Walker, C., Hulme, L., Bernhard, E., Codlin, S., Bähler, J., Allshire, R., Whitehall, S. Humphrey, T.C., (2014). A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice. Nature Communications (5):4091 10.1038/ncomms5091.
K. Jha, D.K., Pfister, S.X., Humphrey, T.C., Strahl, B.D. (2014) SET-ting the stage for DNA repair, Nat Struct Mol Biol, 21, 655-7.
Ahrabi S., Sarkar S., Pfister S.X., Pirovano G., Higgins G.S., Porter A.C.G., Humphrey T.C. (2016) A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic Acids Res. 44, 5743-5757.