The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy

• Published in: Nature genetics Vol. 51; no. 11; pp. 1645 - 1651
• Main Authors: Lindeboom, Rik G. H., Vermeulen, Michiel, Lehner, Ben, Supek, Fran
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2019; Nature Publishing Group
• Subjects: 631/114/2184; 631/208/212; 631/208/457; 631/337/2019; 631/67; Agriculture; Analysis; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer immunotherapy; Cancer Research; Care and treatment; Codons; CRISPR; Deactivation; Decay; Decision making; Development and progression; Disease; Gene Editing; Gene expression; Gene Function; Genetic Diseases, Inborn - genetics; Genetic disorders; Genetic modification; Genome editing; Genomes; Health aspects; Human Genetics; Humans; Immunotherapy; Inactivation; Melanoma; Messenger RNA; Metastasis; Models, Genetic; mRNA turnover; Mutation; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; Nonsense Mediated mRNA Decay - genetics; Nonsense-mediated mRNA decay; Proteins; RNA, Messenger - genetics; Tumors; Spain
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0517-5

Premature termination codons (PTCs) can result in the production of truncated proteins or the degradation of messenger RNAs by nonsense-mediated mRNA decay (NMD). Which of these outcomes occurs can alter the effect of a mutation, with the engagement of NMD being dependent on a series of rules. Here, by applying these rules genome-wide to obtain a resource called NMDetective, we explore the impact of NMD on genetic disease and approaches to therapy. First, human genetic diseases differ in whether NMD typically aggravates or alleviates the effects of PTCs. Second, failure to trigger NMD is a cause of ineffective gene inactivation by CRISPR–Cas9 gene editing. Finally, NMD is a determinant of the efficacy of cancer immunotherapy, with only frameshifted transcripts that escape NMD predicting a response. These results demonstrate the importance of incorporating the rules of NMD into clinical decision-making. Moreover, they suggest that inhibiting NMD may be effective in enhancing cancer immunotherapy.
The authors explore the impact of nonsense-mediated mRNA decay (NMD) on human genetic disease and cancer immunotherapy by applying the rules of NMD across the genome as a resource called NMDetective.