Effect of small molecule eRF3 degraders on premature termination codon readthrough.

Abstract

Premature termination codon (PTC) readthrough is considered a potential treatment for genetic diseases caused by nonsense mutations. High concentrations of aminoglycosides induce low levels of PTC readthrough but also elicit severe toxicity. Identifying compounds that enhance PTC readthrough by aminoglycosides or reduce their toxicity is a continuing challenge. In humans, a binary complex of eukaryotic release factors 1 (eRF1) and 3 (eRF3a or eRF3b) mediates translation termination. They also participate in the SURF (SMG1-UPF1-eRF1-eRF3) complex assembly involved in nonsense-mediated mRNA decay (NMD). We show that PTC readthrough by aminoglycoside G418 is considerably enhanced by eRF3a and eRF3b siRNAs and cereblon E3 ligase modulators CC-885 and CC-90009, which induce proteasomal degradation of eRF3a and eRF3b. eRF3 degradation also reduces eRF1 levels and upregulates UPF1 and selectively stabilizes TP53 transcripts bearing a nonsense mutation over WT, indicating NMD suppression. CC-90009 is considerably less toxic than CC-885 and it enhances PTC readthrough in combination with aminoglycosides in mucopolysaccharidosis type I-Hurler, late infantile neuronal ceroid lipofuscinosis, Duchenne muscular dystrophy and junctional epidermolysis bullosa patient-derived cells with nonsense mutations in the IDUA, TPP1, DMD and COL17A1 genes, respectively. Combination of CC-90009 with aminoglycosides such as gentamicin or ELX-02 may have potential for PTC readthrough therapy.

• Authors: Alireza Baradaran-Heravi, Aruna D Balgi, Sara Hosseini-Farahabadi, Kunho Choi, Cristina Has, Michel Roberge
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 49 Issue 7 Pg. 3692-3708 (04 19 2021) ISSN: 1362-4962 [Electronic] England
• PMID: 33764477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Aminoglycosides
• Codon, Nonsense
• ETF1 protein, human
• Peptide Termination Factors
• Tripeptidyl-Peptidase 1
• peptide-chain-release factor 3
• TPP1 protein, human

Topics

• Aminoglycosides (pharmacology)
• Cell Line
• Codon, Nonsense
• Genetic Diseases, Inborn (genetics, therapy)
• Humans
• Peptide Termination Factors (metabolism)
• Tripeptidyl-Peptidase 1