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Updated: May 1, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense
Leenus Martin1, Arsen Grigoryan1, Ding Wang1
1Authors' Affiliations: Departments of Medicine, Biochemistry and Molecular Pharmacology; The NYU Cancer Institute, New York University School of Medicine; and Departments of Pediatrics and Cell and Biology Development, Weill Cornell School of Medicine, New York, New York.
Abstract:
Many of the gene mutations found in genetic disorders, including cancer, result in premature termination codons (PTC) and the rapid degradation of their mRNAs by nonsense-mediated RNA decay (NMD). We used virtual library screening, targeting a pocket in the SMG7 protein, a key component of the NMD mechanism, to identify compounds that disrupt the SMG7-UPF1 complex and inhibit NMD. Several of these compounds upregulated NMD-targeted mRNAs at nanomolar concentrations, with minimal toxicity in cell-based assays. As expected, pharmacologic NMD inhibition disrupted SMG7-UPF1 interactions. When used in cells with PTC-mutated p53, pharmacologic NMD inhibition combined with a PTC "read-through" drug led to restoration of full-length p53 protein, upregulation of p53 downstream transcripts, and cell death. These studies serve as proof-of-concept that pharmacologic NMD inhibitors can restore mRNA integrity in the presence of PTC and can be used as part of a strategy to restore full-length protein in a variety of genetic diseases.
Insights
Researchers identified compounds that inhibit nonsense-mediated RNA decay (NMD), a process that degrades faulty mRNAs. This approach can restore full-length proteins in genetic disorders and cancer by upregulating NMD-targeted mRNAs.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Gene mutations causing premature termination codons (PTCs) lead to mRNA degradation via nonsense-mediated RNA decay (NMD).
- NMD is a key cellular mechanism involved in genetic disorders and cancer, impacting protein integrity.
Purpose of the Study:
- To identify compounds that inhibit NMD by disrupting the SMG7-UPF1 complex.
- To evaluate the efficacy and safety of NMD inhibitors in cellular models.
Main Methods:
- Virtual library screening targeting the SMG7 protein.
- Cell-based assays to assess mRNA upregulation and toxicity.
- Combination therapy with NMD inhibitors and PTC read-through drugs.
Main Results:
- Identified compounds inhibited NMD at nanomolar concentrations with minimal toxicity.
- Pharmacologic NMD inhibition disrupted SMG7-UPF1 interactions.
- Combination therapy restored full-length p53 protein, upregulated downstream transcripts, and induced cell death in PTC-mutated p53 cells.
Conclusions:
- Pharmacologic NMD inhibition is a viable strategy to restore mRNA integrity in the presence of PTCs.
- NMD inhibitors can be part of a therapeutic approach to restore full-length proteins in genetic diseases and cancer.
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