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, Ziegelmueller, Jana and Teodorowicz, Wojciech (2023) A novel molecule promotes readthrough at premature stop codons by inducing co-translational degradation of eRF1 involving GCN1, RNF14 and RNF25. Cell reports, 42 (Sep 26). pp. 1-30. ISSN 113056

Abstract

Suppression of premature termination codons (PTCs) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two 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 stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, activating a branch of the ribosome-associated 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:	21 Sep 2023 00:45
Last Modified:	21 Sep 2023 00:45
URI:	https://oak.novartis.com/id/eprint/51501