Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs. [ptRNAseq_A2780_Fractionation]

ABSTRACT: Clinically used small molecules have been predicted to off-target to RNAs. However, the extent of this interaction is small molecule cancer therapeutics have not been characterized. Here, we screened for anticancer small molecules for their RNA interactions and uncovered widespread RNA off-targeting. Cisplatin was found to be one among the RNA binders. We used it as a model agent to identify the specific transcripts it interacts with. To accomplish this, we developed Plat-RNAseq, a click-chemistry-mediated transcriptome-wide assay. Our results revealed that cisplatin binding was enriched at guanine-rich regions capable of forming RNA G-quadruplexes (rG4s). We found that the recruitment of cisplatin to rG4s partially contributed to its cytotoxicity, revealing a noncanonical mechanism of action for this widely used chemotherapeutic agent. This experiment applied PlatRNA-seq to chromatin-associated, nuclear and cytoplasmic RNA fractions to assess whether platinum binding occurs co-transcriptionally or on mature RNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE352212 | GEO | 2026/10/27

REPOSITORIES: GEO