Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops
<p>Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O<sub>2</sub>) is one of the few physiologically relevant stresses that activates both the replication stress/DNA d...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2023
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| _version_ | 1797112440141381632 |
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| author | Ma, TS Worth, KR Maher, C Ng, N Beghè, C Gromak, N Rose, AM Hammond, EM |
| author_facet | Ma, TS Worth, KR Maher, C Ng, N Beghè, C Gromak, N Rose, AM Hammond, EM |
| author_sort | Ma, TS |
| collection | OXFORD |
| description | <p>Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O<sub>2</sub>) 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.</p> |
| first_indexed | 2024-03-07T08:25:48Z |
| format | Journal article |
| id | oxford-uuid:2a9d305b-ee6b-4cd7-89c6-e2751f8ccc27 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:25:48Z |
| publishDate | 2023 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:2a9d305b-ee6b-4cd7-89c6-e2751f8ccc272024-02-16T08:00:16ZHypoxia-induced transcriptional stress is mediated by ROS-induced R-loopsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2a9d305b-ee6b-4cd7-89c6-e2751f8ccc27EnglishSymplectic ElementsOxford University Press2023Ma, TSWorth, KRMaher, CNg, NBeghè, CGromak, NRose, AMHammond, EM<p>Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O<sub>2</sub>) 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.</p> |
| spellingShingle | Ma, TS Worth, KR Maher, C Ng, N Beghè, C Gromak, N Rose, AM Hammond, EM Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title | Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title_full | Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title_fullStr | Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title_full_unstemmed | Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title_short | Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops |
| title_sort | hypoxia induced transcriptional stress is mediated by ros induced r loops |
| work_keys_str_mv | AT mats hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT worthkr hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT maherc hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT ngn hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT beghec hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT gromakn hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT roseam hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops AT hammondem hypoxiainducedtranscriptionalstressismediatedbyrosinducedrloops |