The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy
Open accessAbstract
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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When indels are deposited at coding sequences of a given gene, NHEJ can cause frameshift mutations, resulting in non-sense-mediated mRNA decay and gene silencing.
“When the indels are deposited at the coding sequences of a given gene, NHEJ can cause frameshift mutations, resulting in non-sense-mediated mRNA decay and gene silencing (Wang et al., 2016a; Zischewski et al., 2017; Lindeboom et al., 2019).”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Lindeboom et al., 2019
The Results section, “NMD efficacy determines the outcome of gene editing” (page unavailable), says Cas9-induced indels are often frameshifting and can lead to mRNA degradation by NMD, supporting that pathway. It does not identify NHEJ as the cause, and it specifies that some frameshifts instead produce truncated proteins; the Discussion adds that these can leave gene inactivation incomplete. (LLM, conf=0.86)
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References 70 · Cited by 327
Research works printed but not linked: 1
- [57]Karczewski KJ Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes bioRxiv 2019
- Authors
- Lindeboom, R. G. H., Vermeulen, M., Lehner, B., & Supek, F.
- Affiliations
- Radboud University Nijmegen (NL)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Lehner, Ben
- Supek, Fran
- Venue
- Nature Genetics
- Published
- 2019-10-28
- Volume
- 51
- Issue
- 11
- Pages
- 1645-1651
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6858879
- OpenAlex
- W2981514644
- Cited by
- 327
- References
- 70
- Citations by year
- 2026: 48 · 2025: 49 · 2024: 64 · 2023: 48 · 2022: 44 · 2021: 46 · 2020: 26 · 2019: 1 · 2015: 1
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- nonsense-mediated mRNA decay, premature stop codon, genetic disorders, CRISPR/Cas9 genome editing, cancer immunotherapy, truncated protein, mRNA degradation, genome-wide analysis
- MeSH terms
- Gene Editing, Humans, Immunotherapy, Models, Genetic, Neoplasms, RNA, Messenger, Genetic Diseases, Inborn, Nonsense Mediated mRNA Decay
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