Multiple human genetic diseases are caused by premature stop codons located in the messenger RNA, inducing the ribosome to translate over these would be a promising approach to treat these diseases. Researcher from Novartis and the Mühlemann identified two compounds that promote readthrough at Premature Termination Codons and could identify their mode of action. Opposite to other molecules, they do not interefere with the recognition of the stop codon but by triggering degradation of the translation termination factor eRF1. They could show in a rat model of Hurler disease that their approach lowers the glucosamine levels in the brain. Their findings were published in the article "Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control" in Cell Reports.

Highlights

• NVS1.1 and NVS2.1 restore CFTR and IDUA activity in CF and Hurler disease models
• The drugs induce proteasomal eRF1 degradation and readthrough of PTCs
• And block translation termination by trapping eRF1 in the A site, causing ribosome collisions
• GCN1, RNF14, and RNF25 sense occluded A sites and degrade the trapped eRF1

Summary
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, and activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

Read the Publication in Cell Reports (Open Access)

Website Mühlemann Lab

Abstract, figure, highlights and summary from Gurzeler et al (2023) Cell Reports published under a CC BY-NC-ND 4.0 license.