Hypoxia-induced SETX links replication stress with the unfolded protein response

Ramachandran, S.; Ma, T.; Ng, N.; Foskolou, I.; Hwang, M.-S.; Victori, P.; Cheng, W.-C.; Buffa, F. M.; Leszczynska, K.; Gromak, N.; Hammond, E. M.

doi:10.1101/2020.05.24.113548

bioRxiv · 10.1101/2020.05.24.113548

Hypoxia-induced SETX links replication stress with the unfolded protein response

Ramachandran, S.·Ma, T.·Ng, N.·Foskolou, I.·Hwang, M.-S.·Victori, P.·Cheng, W.-C.·Buffa, F. M.·Leszczynska, K.·Gromak, N.·Hammond, E. M.

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Abstract

The levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, we show that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological 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.

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Ramachandran, S., Ma, T., Ng, N., Foskolou, I., Hwang, M.-S., Victori, P., Cheng, W.-C., Buffa, F. M., Leszczynska, K., Gromak, N., Hammond, E. M.. 2020-05-26. Hypoxia-induced SETX links replication stress with the unfolded protein response. https://doi.org/10.1101/2020.05.24.113548

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