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RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning

ABSTRACT: Targeting RNA with small molecules offers a strategy to modulate gene expression at undruggable targets. Traditional screens favor thermodynamically stable, low-entropy RNA motifs with defined conformations, yet these provide limited energetic leverage for functional modulation. Many RNAs instead sample dynamic structural ensembles that small molecules can stabilize or redirect. Using group I self-splicing introns as a model, we identified the antineoplastic drug Mitoxantrone as a competitive inhibitor of RNA self-splicing (IC50 = 4.3 μM) that stabilizes the native conformation of the T4 td intron. Structure-activity analysis showed the anthraquinone scaffold alone is insufficient, and basic amine side chains are required for RNA structural modulation. Transcriptome-wide chemical probing in human cells revealed preferential binding to GC-rich structured regions, although only a subset showed structural change. Furthermore, global analysis of 5′ UTR ensembles showed reduced structural heterogeneity and increased translation, demonstrating functional repartitioning of RNA conformational landscapes.

ORGANISM(S): Homo sapiens Escherichia phage T4

PROVIDER: GSE302505 | GEO | 2026/02/17

REPOSITORIES: GEO

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