Investigating the effect of ionising radiation on cyclic hypoxia-induced replication catastrophe and genome instability in tumours

Our previous research has demonstrated that cells exposed to severe levels of hypoxia (<0.1% O2) experience replication stress which in turn leads to a DNA damage response (DDR). The study of the hypoxia-induced DDR has illuminated potential therapeutic strategies to target hypoxic cells in tumours. This is an important goal as it is the hypoxic fraction of tumours which are most resistant to radiotherapy and lead to tumour reoccurrence and poor prognosis. Most recently, we have become aware that the DDR is also impacted by an addition al stress response induced in response to severe hypoxia, the unfolded protein response (UPR). Despite this knowledge however, we have failed to consider the fluctuation in oxygen levels experienced by cancer cells (cyclic hypoxia) and have tended to carry out experiments in constant levels of oxygen which do not accurately mimic the tumour. This project will focus on the understanding of the interaction of the DDR and UPR in cells exposed to radiation and importantly, how this is impacted by physiologically relevant oxygen conditions.