Hypoxia-induced SETX links replication stress with the unfolded protein response
CLINICAL CANCER RESEARCH(2020)
摘要
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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关键词
Hypoxia,Replication stress,UPR,SETX,R-loops,RNA/DNA hybrids
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