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Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs [ChIP-seq]

ABSTRACT: Small molecules developed to target proteins and DNA may also bind RNA, but the extent and biological significance of these interactions remain poorly defined. Here, we systematically profiled RNA interactions of clinically approved chemotherapeutics and uncovered widespread RNA off-targeting. Cisplatin, a frontline chemotherapeutic for solid tumors, emerged as a prominent RNA-binding drug. To map these interactions in vivo, we developed Plat-RNAseq, a click-chemistry-mediated transcriptome-wide assay. Cisplatin binding was enriched at guanine-rich regions capable of forming RNA G-quadruplexes (rG4s) and preferentially accumulated at the 5′ ends of nascent transcripts that exhibited rG4 enrichment and R-loop formation. Cisplatin stabilized pre-formed rG4s while interfering with their de novo assembly, thereby altering RNA structure and function. The recruitment of cisplatin to rG4s contributed to its cytotoxicity, revealing a noncanonical mechanism of action for this widely used chemotherapeutic agent. Consistent with this mechanism, the expression level of rG4 cisplatin-RNA targets predicted the platinum sensitivity in ovarian cancer patients. Collectively, these findings broaden platinum pharmacology by revealing RNA interactions as a functionally relevant, non-canonical component of cisplatin’s mechanism of action. Our study highlights the importance of incorporating RNA interactions into drug design and establishes a framework for considering RNA as a functionally relevant target in small-molecule therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309934 | GEO | 2026/02/23

REPOSITORIES: GEO

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Project description:RNA structures are of crucial importance for biological function and gene regulation. Guanine (G)-rich sequences in RNA can assemble to form RNA G-quadruplex (rG4) structures; specific rG4s have been shown to regulate gene expression, and are associated with human diseases. However, no transcriptome-wide method has been reported to map rG4s, limiting our understanding of the rG4 structure and its relationship with function and regulation. Here we introduce a transcriptome-wide rG4 profiling method, rG4-Seq, in which the rG4-mediated reverse transcriptase stalling is read out by next-generation sequencing at nucleotide resolution. We apply this method to human RNA and report the first global map of rG4 structures for any organism. Our analysis identifies over 3,000 rG4s, and increases to over 11,000 upon addition of a rG4 stabilizing ligand Pyridostatin (PDS). Notably, we discover that besides canonical rG4s, many rG4s are non-canonical with novel structural features such as long-loops, bulges, and 2-quartet. We also find that rG4 formation is associated with its stability, Cytosine (C)-content, and the stability of alternative RNA structures. Our data reveals that rG4s can be found in messenger RNAs (mRNAs) and long intergenic noncoding RNAs (lincRNAs). In mRNAs, rG4s are enriched in untranslated regions, and are significantly correlated with microRNA target sites and polyadenylation signals. Remarkably, we found that majority of our in vitro identified rG4s can change the in silico predicted RNA structure to uncover alternative RNA conformation.. Futhermore, the rG4s that have analogues in many ortholog genes across different species show a preferential association with RNA processing and stability. rG4-seq is a broadly applicable method that enables the RNA G4 structurome and its biological roles to be interrogated and can be readily applied in other organisms on a transcriptome-wide scale. 12 samples, 150 bp single-ended RNA-Seq libraries from cell extracts after performing RTS reaction in different buffers (Li, K and K+PDS rich buffer). Each of the 3 conditions has 4 libraries from independent biological replicates.

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Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs [ChIP-seq]

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