Nonsense-mediated decay in genetic disease: Friend or foe?

Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRN...

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Bibliographic Details
Published in:Mutation research. Reviews in mutation research 2014-10, Vol.762, p.52-64
Main Authors: Miller, Jake N., Pearce, David A.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Disease - classification
Disease - genetics
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation
Genetic disease
Humans
Molecular and cellular biology
Molecular genetics
Mutagenesis. Repair
Nonsense Mediated mRNA Decay
Nonsense suppression
Nonsense-mediated decay
Organ Specificity
Read-through
RNA, Messenger - metabolism
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Summary:Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.
ISSN:1383-5742
1388-2139
DOI:10.1016/j.mrrev.2014.05.001