TY - JOUR
T1 - Identification and characterization of small molecules that inhibit nonsense-mediated rna decay and suppress nonsense p53 mutations
AU - Martin, Leenus
AU - Grigoryan, Arsen
AU - Wang, Ding
AU - Wang, Jinhua
AU - Breda, Laura
AU - Rivella, Stefano
AU - Cardozo, Timothy
AU - Gardner, Lawrence B.
PY - 2014/6/1
Y1 - 2014/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-13-2235
DO - 10.1158/0008-5472.CAN-13-2235
M3 - Article
C2 - 24662918
AN - SCOPUS:84902125654
SN - 0008-5472
VL - 74
SP - 3104
EP - 3113
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -