Identification and characterization of small molecules that inhibit nonsense-mediated rna decay and suppress nonsense p53 mutations

Leenus Martin, Arsen Grigoryan, Ding Wang, Jinhua Wang, Laura Breda, Stefano Rivella, Timothy Cardozo, Lawrence B. Gardner

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Many of the gene mutations found in genetic disorders, including cancer, result in premature termination codons (PTC) and the rapid degradation of theirmRNAs by nonsense-mediatedRNAdecay(NMD).Weused 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.

Original languageEnglish (US)
Pages (from-to)3104-3113
Number of pages10
JournalCancer Research
Volume74
Issue number11
DOIs
StatePublished - Jun 1 2014

Bibliographical note

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'Identification and characterization of small molecules that inhibit nonsense-mediated rna decay and suppress nonsense p53 mutations'. Together they form a unique fingerprint.

Cite this