The nucleoside analog clitocine is a potent and efficacious readthrough agent.

Abstract

Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog clitocine as a potent and efficacious suppressor of nonsense mutations. We determined that incorporation of clitocine into RNA during transcription is a prerequisite for its readthrough activity; the presence of clitocine in the third position of a premature stop codon directly induces readthrough. We demonstrate that clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. In these cells, clitocine restored production of full-length and functional p53 as evidenced by induced transcriptional activation of downstream p53 target genes, progression of cells into apoptosis, and impeded growth of nonsense-containing human ovarian cancer tumors in xenograft tumor models. Thus, clitocine induces readthrough of nonsense mutations by a previously undescribed mechanism and represents a novel therapeutic modality to treat cancers and genetic diseases caused by nonsense mutations.

• Authors: Westley J Friesen, Christopher R Trotta, Yuki Tomizawa, Jin Zhuo, Briana Johnson, Jairo Sierra, Bijoyita Roy, Marla Weetall, Jean Hedrick, Josephine Sheedy, James Takasugi, Young-Choon Moon, Suresh Babu, Ramil Baiazitov, John D Leszyk, Thomas W Davis, Joseph M Colacino, Stuart W Peltz, Ellen M Welch
• Journal: RNA (New York, N.Y.) (RNA) Vol. 23 Issue 4 Pg. 567-577 (04 2017) ISSN: 1469-9001 [Electronic] United States
• PMID: 28096517 (Publication Type: Journal Article)
• Copyright: © 2017 Friesen et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Chemical References

• Antimetabolites, Antineoplastic
• Codon, Nonsense
• Furans
• Nucleosides
• Pyrimidine Nucleosides
• Tumor Suppressor Protein p53
• clitocine
• Luciferases

Topics

• Animals
• Antimetabolites, Antineoplastic (chemical synthesis, metabolism, pharmacology)
• Apoptosis (drug effects)
• Biomimetic Materials (chemical synthesis, metabolism, pharmacology)
• Cell Line, Tumor
• Codon, Nonsense (drug effects)
• Female
• Furans (chemical synthesis, metabolism, pharmacology)
• Genes, Reporter
• Humans
• Luciferases (genetics, metabolism)
• Mice
• Mice, Nude
• Nucleosides (chemical synthesis, metabolism, pharmacology)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Biosynthesis
• Pyrimidine Nucleosides (chemical synthesis, metabolism, pharmacology)
• Signal Transduction
• Transcriptional Activation
• Tumor Burden (drug effects)
• Tumor Suppressor Protein p53 (agonists, genetics, metabolism)
• Xenograft Model Antitumor Assays