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Primary Supervisor: Professor Ester Hammond

Project Overview:

Regions of low oxygen or hypoxia occur in most solid tumours and predict for a poor patient outcome. Cancer cells adapt to hypoxic conditions and become resistant to therapy, therefore finding new strategies to target tumour hypoxia is essential to improve patient care. Recent transcriptomic studies of hypoxic tumours have identified an upregulation of viral restriction factors. These data lead us to hypothesise a common sensing pathway for cells to respond to the stress of hypoxia or viral infection. This project will begin with a detailed analysis of the available RNA sequencing data to identify genes involved in both the hypoxia and viral response. In parallel, we will focus on the E3 ubiquitin-ligase, TRIM5 which is a retroviral restriction factor and, a gene that we have recently found to be hypoxia-inducible. The project will elucidate the mechanism of TRIM5 induction in hypoxia and to determine if this is shared with the response to viral infection. The project opens collaborative opportunities between groups working in tumour microenvironment and virology.

Training Opportunities:

• Develop an extensive skill set in Cell Biology, Molecular Biology, Transcriptomics and Tissue Culture.

• Experience working in a collaborative team environment and presenting data at internal lab meetings, journal clubs and seminars. Includes close collaboration with Prof Jane McKeating (expert on viral replication)

• Contribute data towards publication in a peer reviewed journal.

Relevant Publications:

Leszczynska, K.B., Dzwigonska, M., Estephan, H., Moehlenbrink, J., Bowler, E., Giaccia, A.J., Mieczkowski, J., Kaminska, B. and Hammond, E.M., 2022. Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation. bioRxiv.

Bader, S.B., Ma, T.S., Simpson, C.J., Liang, J., Maezono, S.E.B., Olcina, M.M., Buffa, F.M. and Hammond, E.M., 2021. Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity. Nucleic acids research49(13), pp.7492-7506.

Ramachandran, S., Ma, T.S., Griffin, J., Ng, N., Foskolou, I.P., Hwang, M.S., Victori, P., Cheng, W.C., Buffa, F.M., Leszczynska, K.B. and El-Khamisy, S.F., 2021. Hypoxia-induced SETX links replication stress with the unfolded protein response. Nature Communications12(1), pp.1-14.