Hypoxia‐mediated regulation of DDX5 through decreased chromatin accessibility and post‐translational targeting restricts R‐loop accumulation

Autor: Katarzyna B. Leszczynska, Monika Dzwigonska, Hala Estephan, Jutta Moehlenbrink, Elizabeth Bowler, Amato J. Giaccia, Jakub Mieczkowski, Bozena Kaminska, Ester M. Hammond
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecular Oncology, Vol 17, Iss 7, Pp 1173-1191 (2023)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.13431
Popis: 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 DDX5, 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.
Databáze: Directory of Open Access Journals
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