Control of gene expression through the nonsense-mediated RNA decay pathway

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Abstract

Nonsense-mediated RNA decay (NMD) was originally discovered as a cellular surveillance pathway that safeguards the quality of mRNA transcripts in eukaryotic cells. In its canonical function, NMD prevents translation of mutant mRNAs harboring premature termination codons (PTCs) by targeting them for degradation. However, recent studies have shown that NMD has a much broader role in gene expression by regulating the stability of many normal transcripts. In this review, we discuss the function of NMD in normal physiological processes, its dynamic regulation by developmental and environmental cues, and its association with human disease.

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Most cited references 137

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Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes.

Søren Lykke-Andersen, Torben Heick Jensen (2015)

Nonsense-mediated mRNA decay (NMD) is probably the best characterized eukaryotic RNA degradation pathway. Through intricate steps, a set of NMD factors recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts. However, NMD is not only part of a general cellular quality control system that prevents the production of aberrant proteins. Mammalian cells also depend on NMD to dynamically adjust their transcriptomes and their proteomes to varying physiological conditions. In this Review, we discuss how NMD targets mRNAs, the types of mRNAs that are targeted, and the roles of NMD in cellular stress, differentiation and maturation processes.

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Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

Cristina Barbosa, Isabel Peixeiro, Luísa Romão (2013)

Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.

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Nonsense-mediated mRNA decay in humans at a glance.

Tatsuaki Kurosaki, Lynne Maquat (2016)

Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor up-frameshift protein 1 (UPF1).

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Author and article information

Contributors

Andrew Nickless: nickless_a@wustl.edu

Julie M. Bailis: jbailis@amgen.com

Zhongsheng You:

ORCID: http://orcid.org/0000-0002-9719-8791

314-362-9893 , zyou@wustl.edu

Journal

Journal ID (nlm-ta): Cell Biosci

Journal ID (iso-abbrev): Cell Biosci

Title: Cell & Bioscience

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-3701

Publication date (Electronic): 19 May 2017

Publication date PMC-release: 19 May 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 26

Affiliations

[1 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Cell Biology & Physiology, , Washington University School of Medicine, ; Campus Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110 USA

[2 ]ISNI 0000 0001 0657 5612, GRID grid.417886.4, Department of Oncology Research, , Amgen, ; South San Francisco, CA 94080 USA

Author information

Zhongsheng You http://orcid.org/0000-0002-9719-8791

Article

Publisher ID: 153

DOI: 10.1186/s13578-017-0153-7

PMC ID: 5437625

PubMed ID: 28533900

SO-VID: 9fb9ca79-188f-40f9-8795-81921470579a

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 January 2017

Date accepted : 12 May 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: R01GM098535

Award Recipient : Zhongsheng You

Funded by: FundRef http://dx.doi.org/10.13039/100000048, American Cancer Society;

Award ID: RSG-13-212-01-DMC

Award Recipient : Zhongsheng You

Funded by: FundRef http://dx.doi.org/10.13039/100009340, Children's Discovery Institute;

Award ID: MC-II-2012-215

Award Recipient : Zhongsheng You

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ScienceOpen disciplines: Cell biology

Keywords: nonsense-mediated decay,rna surveillance,gene expression,human disease

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ScienceOpen disciplines: Cell biology

Keywords: nonsense-mediated decay, rna surveillance, gene expression, human disease

Control of gene expression through the nonsense-mediated RNA decay pathway

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Most cited references 137

Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes.

Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

Nonsense-mediated mRNA decay in humans at a glance.

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