Characterisation of the cross-talk between the hypoxia-induced DNA damage and unfolded protein responses

Primary Supervisor: Professor Ester Hammond

Second Supervisor: Dr Monica Olcina

Day-to-day supervision: Dr Bozhena Caratti

Project Overview

Conditions of low oxygen (hypoxia) occur to some degree in most solid tumours. The presence of hypoxia is significant as it is well established that hypoxia leads to treatment resistance and poor patient prognosis. Our focus is the levels of hypoxia which lead to problems with DNA replication/transcription and protein folding. This level of hypoxia is characterised by a robust induction of the DNA damage response (DDR) and unfolded protein response (UPR). Increasingly, links between the DDR and UPR have been elucidated. This project will take a mechanism-based approach to describing links between the DDR and UPR in hypoxia with the goal of identifying new potential therapeutic targets and strategies.

Training Opportunities

The majority of the research carried out is molecular or cell biology (see recent papers for examples). However, we take a multi-disciplinary approach wherever possible to achieve our goals including working with clinicians, chemists and mathematicians.

References 

Ma, T.S., Worth, K.R., Maher, C., Ng, N., Beghè, C., Gromak, N., Rose, A.M. and Hammond, E.M., 2023. Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops. Nucleic acids research, 51(21), pp.11584-11599.

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 research, 49(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 Communications, 12(1), p.3686.