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.
Highlights
Tumour hypoxia is associated with poor patient prognosis and therapy resistance
We found that the loss of SETX leads to an accumulation of R-loops, and that hypoxia-induced SETX protected cells from replication stress, transcription-dependent DNA damage and apoptosis
We looked for evidence of links between hypoxia and SETX in cancer patients, using The Cancer Genome Atlas (TCGA) colorectal and lung cancers datasets
Summary
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. We propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response These data 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. Hypoxia-induced replication stress leads to the induction of an ATR- and ATM-dependent DNA damage response (DDR), hypoxia-induced replication stress is insufficient to induce ATM-mediated signalling and increased levels of heterochromatic histone marks, notably H3K9me[3] are required[5,6,7] Both hypoxiainduced ATR and ATM activity occur in the absence of detectable DNA damage[8]. We found that the loss of SETX leads to an accumulation of R-loops, and that hypoxia-induced SETX protected cells from replication stress, transcription-dependent DNA damage and apoptosis. Hypoxia-induced SETX was dependent on the PERK branch of the UPR, suggestive of a link between the UPR and replication stress in hypoxia
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