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Hypoxia-induced SETX links replication stress with the unfolded protein response
Ramachandran, S. Ma, T.S. Griffin, J. Ng, N. Foskolou, I.P. Hwang, M-S. Victori, P. Cheng, W-C. Buffa, F.M. Leszczynska, K.B.
Ramachandran, S.
Ma, T.S.
Griffin, J.
Ng, N.
Foskolou, I.P.
Hwang, M-S.
Victori, P.
Cheng, W-C.
Buffa, F.M.
Leszczynska, K.B.
Publication Date
2021
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(c) 2021 The authors. This article is licensed under a Creative Commons
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2021-05-31
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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.
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Citation
Ramachandran S, Ma TS, Griffin J et al (2021) Hypoxia-induced SETX links replication stress with the unfolded protein response. Nature Communications. 12: 3686.
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Article