Journal
NATURE GENETICS
Volume 51, Issue 11, Pages 1645-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-019-0517-5
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Funding
- ERC Starting Grant HYPER-INSIGHT [757700]
- ERC Consolidator Grant IR-DC [616434]
- Oncode Institute - Dutch Cancer Society
- Netherlands Organization for Scientific Research
- Severo Ochoa Centres of Excellence programme
- Spanish Ministry of Economy and Competitiveness [BFU2017-89488-P, BFU2017-89833-P]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca [2017 SGR 1322]
- CERCA Program/Generalitat de Catalunya
- Spanish Ministry of Economy, Industry and Competitiveness
- Bettencourt Schueller Foundation
- ICREA Research Professor programme
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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.
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