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Hypoxia links the unfolded proteim response with the DNA damage response


Project Description

THE PROJECT
Regions of hypoxia (insufficient oxygen) occur in most if not all solid tumours and are clinically relevant as they correlate with poor patient prognosis and therapy resistance. The extreme levels of hypoxia (<0.1% O2) found bordering the necrotic regions of tumours lead to the rapid accumulation of replication stress. We have recently attributed hypoxia induced replication stress, at least in part, to the oxygen dependency of nucleotide synthesis and specifically the ribonucleotide reductase enzyme. Hypoxia-induced replication stress initiates a DNA damage response (DDR), which is unique as it does not include detectable DNA damage. The outcome of this hypoxia-induced signalling includes p53-dependent apoptosis through the transactivation of a specific set of target genes and the protection of stalled replication forks. Notably, the hypoxia-induced DDR occurs in a complex environment which includes epigenetic changes, reduced DNA repair, activation of the unfolded protein response (UPR) and global repression of transcription. Recently, we have uncovered novel links between the PERK/ATF4 arm of the UPR and the biological response to DNA damage/replication stress. Specifically, we found that the putative DNA/RNA helicase Senataxin (SETX) is induced in a PERK/ATF dependent manner in response to hypoxia. Loss of SETX in these conditions led to an accumulation of aberrant transcription structures (R-loops), DNA damage and loss of viability. Our hypothesis is that it is highly unlikely that SETX is the only gene regulated in this way in response to hypoxia and indeed we have preliminary data to demonstrate this is the case. This project will therefore focus on exploring the links between the UPR and DDR in the physiological relevant conditions of tumour hypoxia. This project will include a broad range of cell biological, molecular and biochemical techniques.

THE TRAINING
We have a number of local collaborators who are experts in the fields of R-loop biology (Natalia Gromak) and transcription (Shona Murphy) as well and the second supervisor (Amato Giaccia) who brings decades of experience of hypoxia/UPR research. The Hammond group has a track record of taking a multi-disciplinary approach in order to generate high impact findings, for example the recent paper from a student in my lab (Iosifina Foskolou) involved collaborations in Computations biology, Chemistry and Earth Sciences.

PUBLICATIONS
Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication. Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, D’Angiolella V, Myers WK, Domene C, Flashman E, Hammond EM. Mol Cell. 2017 Apr 20;66(2):206-220.

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. Katarzyna B. Leszczynska, Iosifina P. Foskolou, Aswin G. Abraham, Selvakumar Anbalagan, Céline Tellier, Syed Haider, Paul N. Span, Eric E. O’Neill, Francesca M. Buffa and Ester M. Hammond. J Clin Invest. 2015Jun 1;125(6):2385-2398.

Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication. Olcina MM, Foskolou IP, Anbalagan S, Senra JM, Pires IM, Jiang Y, Ryan AJ, Hammond EM. Mol Cell. 2013 Dec 12;52(5):758-66.

Funding Notes

All complete applications received by 12 noon (UK time) on Friday 11 January 2020 will automatically be considered for all relevant competitive University and funding opportunities, including the Clarendon Fund, Medical Research Council funding, and various College funds. Please refer to the Funding and Costs webpage (View Website) for this course for further details relating to funded scholarships and divisional funding opportunities.

Funded studentships are highly competitive and are awarded to the highest ranked applicant(s) based on the advertised entry requirements for each programme of study.

References

Whilst you must register three referees, the department may start the assessment of your application if two of the three references are submitted by the course deadline and your application is otherwise complete. Please note that you may still be required to ensure your third referee supplies a reference for consideration.

Academic references are strongly encouraged, though you may use up to one professional reference provided that it is relevant to the course.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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