Journal
CANCER RESEARCH
Volume 74, Issue 11, Pages 3104-3113Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2235
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Funding
- National Center for the Advancement of Translational Science (NCATS), NIH [RO1DK081641, 1DP2OD004631, UL1 TR000038]
- European Community
- Children's Cancer and Blood Foundation
- [R01HL102449]
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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. (C) 2014 AACR.
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