Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops

Abstract Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication stress/DNA damage response and the unfo...

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Published in:Nucleic acids research Vol. 51; no. 21; pp. 11584 - 11599
Main Authors: Ma, Tiffany S, Worth, Katja R, Maher, Conor, Ng, Natalie, Beghè, Chiara, Gromak, Natalia, Rose, Anna M, Hammond, Ester M
Format: Journal Article
Language:English
Published: England Oxford University Press 27.11.2023
Subjects:
DNA, Ribosomal - genetics
DNA, Ribosomal - metabolism
Humans
R-Loop Structures
Reactive Oxygen Species - metabolism
RNA Polymerase I - metabolism
Transcription, Genetic
Tumor Hypoxia
ISSN:0305-1048, 1362-4962, 1362-4962
Online Access:Get full text
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Summary:Abstract Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication stress/DNA damage response and the unfolded protein response. Recently, we found that hypoxia also leads to the robust accumulation of R-loops, which led us to question here both the mechanism and consequence of hypoxia-induced R-loops. Interestingly, we found that the mechanism of R-loop accumulation in hypoxia is dependent on non-DNA damaging levels of reactive oxygen species. We show that hypoxia-induced R-loops play a critical role in the transcriptional stress response, evidenced by the repression of ribosomal RNA synthesis and the translocation of nucleolin from the nucleolus into the nucleoplasm. Upon depletion of R-loops, we observed a rescue of both rRNA transcription and nucleolin translocation in hypoxia. Mechanistically, R-loops accumulate on the rDNA in hypoxia and promote the deposition of heterochromatic H3K9me2 which leads to the inhibition of Pol I-mediated transcription of rRNA. These data highlight a novel mechanistic insight into the hypoxia-induced transcriptional stress response through the ROS–R-loop–H3K9me2 axis. Overall, this study highlights the contribution of transcriptional stress to hypoxia-mediated tumorigenesis. Graphical Abstract Graphical Abstract
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ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkad858