Hypoxia links the unfolded proteim response with the DNA damage response
Nominating Supervisor: Ester Hammond
Second Supervisor: Amato Giaccia
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.
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.
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.