Hypoxia-induced SETX links replication stress with the unfolded protein response
Shaliny Ramachandran, Stephen T. Tiffany, Jon Griffin, Natalie Ng, Iosifina P. Foskolou, Ming‐Shih Hwang, Pedro Victori, Wei‐Chen Cheng, Francesca M. Buffa, Katarzyna B. Leszczyńska, Sherif F. El‐Khamisy, Natalia Gromak, Ester M. Hammond
Abstract
Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.