Characterising novel roles for ATM in the response to tumour hypoxia

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One of the major limitations of radiotherapy is the dependence on oxygen for radiation-induced DNA damage. The hypoxic (low oxygen) cells within a tumour can withstand 2-3 times the radiation dose of the cells at normal oxygen levels. The focus of the Hammond lab is to investigate the biological response to hypoxia so that we can, a) learn more about the signalling pathways and in particular the DNA damage response (DDR) in these physiologically relevant conditions and b) translate this information into novel therapeutic approaches to improve radiotherapy response (Olcina et al., Clin Can Res 2010). 

We have shown that hypoxia induces replication stress as well as specific chromatin modifications and that the consequence of this is DDR signalling, including both the ATM and ATR kinases (Olcina et al., Oncogene 2015, Foskolou et al., Mol Cell 2017). Once active, the hypoxia-induced DDR leads to p53-dependent apoptosis, although this is lost in the majority of tumours due to the mutation of p53 (Leszczynska et al., JCI 2015). We recently demonstrated a novel role for ATM in DNA replication, although the exact mechanism behind this remains unclear and will be the focus of this DPhil studentship (Olcina et al., Mol Cell 2013). Secondary supervision will be provided by David Clynes.

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