Reinhardt, Juergen, Link, Marion, Ibig-Rehm, Yvonne, Schmidt, Isabel, Galuba, Olaf, Schoenbett, Julian, Gasser-Didierlaurent, Christelle, Parker, Christian, Mao, Xiaohong, Bitsch, Francis, Couttet, Philippe, Sigoillot, Frederic, Schirle, Markus, Schmiedeberg, Niko, Muehlemann, Oliver, Gurzeler, Lukas-Adrian, Uldry, Anne-Christine and Ziegelmueller, Jana (2023) A novel molecule promotes readthrough at premature stop codons by inducing co-translational degradation of eRF1 involving GCN1, RNF14 and RNF25. Cell reports, 26 (42). pp. 1-30. ISSN 2211-1247

Abstract

Drugs that promote translational readthrough at premature termination codons (PTC) are a promising for treating a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two novel and potent readthrough promoters – NVS1.1 and NVS2.1 – that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect decoding of the stop codon, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Interestingly, this appears to occur by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, which activate a novel branch of the ribosome quality control (RQC) network that involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25

Item Type:	Article
Keywords:	Readthrough promoter; Hurler syndrome; IDUA; cystic fibrosis; CFTR; eRF1; ubiquitination; proteasomal degradation; E3 ligase; RNF14; RNF25; GCN1; ribosome collisions, RQC
Date Deposited:	23 Nov 2023 00:45
Last Modified:	23 Nov 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49291