Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation
<p>Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those tha...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2023
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| _version_ | 1797110136723996672 |
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| author | Leszczynka, K Dzwigonska, M Estephan, H Moehlenbrink, J Bowler, E Giaccia, A Mieczkowski, J Kaminska, B Hammond, E |
| author_facet | Leszczynka, K Dzwigonska, M Estephan, H Moehlenbrink, J Bowler, E Giaccia, A Mieczkowski, J Kaminska, B Hammond, E |
| author_sort | Leszczynka, K |
| collection | OXFORD |
| description | <p>Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those that are decreased in hypoxia. We demonstrate that chromatin accessibility is decreased in hypoxia, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing, and the R-loop interactome. One of the genes with decreased chromatin accessibility in hypoxia was <em>DDX5</em>, encoding the RNA helicase, DDX5, which showed reduced expression in various cancer cell lines in hypoxic conditions, tumor xenografts, and in patient samples with hypoxic tumors. Most interestingly, we found that when DDX5 is rescued in hypoxia, replication stress and R-loop levels accumulate further, demonstrating that hypoxia-mediated repression of DDX5 restricts R-loop accumulation. Together these data support the hypothesis that a critical part of the biological response to hypoxia is the repression of multiple R-loop processing factors; however, as shown for DDX5, their role is specific and distinct.</p> |
| first_indexed | 2024-03-07T07:51:27Z |
| format | Journal article |
| id | oxford-uuid:08dbf021-2cc1-4b57-b46c-4e6f6976bc60 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:51:27Z |
| publishDate | 2023 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:08dbf021-2cc1-4b57-b46c-4e6f6976bc602023-07-24T09:37:01ZHypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:08dbf021-2cc1-4b57-b46c-4e6f6976bc60EnglishSymplectic ElementsWiley 2023Leszczynka, KDzwigonska, MEstephan, HMoehlenbrink, JBowler, EGiaccia, AMieczkowski, JKaminska, BHammond, E<p>Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those that are decreased in hypoxia. We demonstrate that chromatin accessibility is decreased in hypoxia, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing, and the R-loop interactome. One of the genes with decreased chromatin accessibility in hypoxia was <em>DDX5</em>, encoding the RNA helicase, DDX5, which showed reduced expression in various cancer cell lines in hypoxic conditions, tumor xenografts, and in patient samples with hypoxic tumors. Most interestingly, we found that when DDX5 is rescued in hypoxia, replication stress and R-loop levels accumulate further, demonstrating that hypoxia-mediated repression of DDX5 restricts R-loop accumulation. Together these data support the hypothesis that a critical part of the biological response to hypoxia is the repression of multiple R-loop processing factors; however, as shown for DDX5, their role is specific and distinct.</p> |
| spellingShingle | Leszczynka, K Dzwigonska, M Estephan, H Moehlenbrink, J Bowler, E Giaccia, A Mieczkowski, J Kaminska, B Hammond, E Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title | Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title_full | Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title_fullStr | Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title_full_unstemmed | Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title_short | Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation |
| title_sort | hypoxia mediated regulation of ddx5 through decreased chromatin accessibility and post translational targeting restricts r loop accumulation |
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