C71
The role of ATM in the response to low oxygen conditions
Ester Hammond
Oxford University, Oxford, UK
Background
All solid tumours experience levels of low oxygen or hypoxia. This is clinically relevant as many studies have shown that the degree of tumour hypoxia correlates with a poor patient prognosis. The degree of tumour hypoxia varies as a result of time and oxygen concentration. Our interest is focused on how severe levels of hypoxia induce a DNA damage response that is mediated by both the ATM and ATR PI3 kinases.
Method
We have relied on standard cell biology and biochemical techniques to elucidate the ATM/ATR signalling in response to hypoxia.
Results
Both ATM and ATR are activated at oxygen levels between 0 and 0.2%. This was determined by the ability to phosphorylate downstream target molecules. Loss of either ATM or ATR sensitises cells to periods of hypoxia followed by reoxygenation. Interestingly, the ATM response to hypoxia differs significantly from the response to DNA damaging agents such as irradiation. For example hypoxia-induced activation of ATM is independent of the MRN complex and the activated ATM does not form the classic nuclear foci observed after DNA damage. A comparison will be made of the hypoxic response versus DNA damage.
Conclusion
Hypoxia represents a physiologically relevant stress which directly impacts patient prognosis. Much effort is being spent on determining therapeutic strategies to sensitise cells to conditions of low oxygen and subsequent reoxygenation. Characterisation of the signalling pathways initiated by ATM will identify novel potential therapeutic targets.
