Molecular profiling of individual FDA-approved clinical drugs identifies modulators of nonsense-mediated mRNA decay

Abstract

Nonsense-mediated mRNA decay (NMD) degrades transcripts with premature stop codons. Given the prevalence of nonsense single nucleotide polymorphisms (SNPs) in the general population, it is urgent to catalog the effects of clinically approved drugs on NMD activity: any interference could alter the expression of nonsense SNPs, inadvertently inducing adverse effects. This risk is higher for patients with disease-causing nonsense mutations or an illness linked to dysregulated nonsense transcripts. On the other hand, hundreds of disorders are affected by cellular NMD efficiency and may benefit from NMD-modulatory drugs. Here, we profiled individual FDA-approved drugs for their impact on cellular NMD efficiency using a sensitive method that directly probes multiple endogenous NMD targets for a robust readout of NMD modulation. We found most FDA-approved drugs cause unremarkable effects on NMD, while many elicit clear transcriptional responses. Besides several potential mild NMD modulators, the anticancer drug homoharringtonine (HHT or omacetaxine mepesuccinate) consistently upregulates various endogenous NMD substrates in a dose-dependent manner in multiple cell types. We further showed translation inhibition mediates HHT's NMD effect. In summary, many FDA drugs induce transcriptional changes, and a few impact global NMD, and direct measurement of endogenous NMD substrate expression is robust to monitor cellular NMD.

Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis

“…Nonsense-mediated mRNA decay is a critical cellular surveillance mechanism, the enrichment of which underscores potential genetic contributions to AV stenosis and represents a novel avenue for repurposing therapeutic nonsense-mediated mRNA decay inhibition. 34 Electron microscopy has shown calcified EVs to be present in mineralized regions of both tissues, 8,14 consistent with the substantial enrichment of vesicle ontologies shared by the disease-altered proteomes of carotid arteries and AVs.…”

Mapping genetic variants for nonsense-mediated mRNA decay regulation across human tissues

“…In mammalian cells, alternative splicing coupled to nonsense-mediated decay (i.e., AS-NMD) is a conserved post-transcriptional regulation mechanism in which alternative splicing can alter the reading frame to produce a PTC-containing transcript subject to NMD [24,[55][56][57][58][59].…”

“…Our own analysis of the GENCODE annotation showed that about 12% of natural transcripts are presumably targeted by NMD regulation, since they follow the 50-nt rule (i.e., the presence of a terminal codon >50 nt upstream of the last exon-exon junction). Accordingly, NMD factors are implicated in cellular homeostasis, stress response, cell cycle, differentiation, development, neural activity, immunity, and spermatogenesis [15][16][17][18][19][20][21][22][23][24]. NMD typically downregulates its substrate by 2-20 folds [25,26], generating significant functional and clinical implications.…”

Diverse Roles of the Exon Junction Complex Factors in the Cell Cycle, Cancer, and Neurodevelopmental Disorders-Potential for Therapeutic Targeting

“…Cardiac glycosides target Na-K ATPase on the cell membrane to increase intracellular Ca2 + levels and inhibit NMD [ 101 ]. Through profiling multiple endogenous NMD targets, Zhao et al identified several NMD modulators, including the anticancer drug homoharringtonine [ 102 ]. Given the diversity of methods that can be used to suppress NMD, NMD inhibition holds a promising therapeutic potential for ameliorating a variety of disease phenotypes.…”