Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges

doi:10.1016/J.MOLMED.2006.05.005

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Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges

Journal Article•DOI•

Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges

Holly Kuzmiak¹, Lynne E. Maquat¹•Institutions (1)

University of Rochester¹

01 Jul 2006-Trends in Molecular Medicine (Trends Mol Med)-Vol. 12, Iss: 7, pp 306-316

TL;DR: How to determine which PTCs elicit NMD is reviewed, what is currently known about the mechanism of NMD, and additional information that is pertinent to establishing therapies for PTC-associated diseases are reviewed.

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About: This article is published in Trends in Molecular Medicine.The article was published on 2006-07-01. It has received 241 citations till now. The article focuses on the topics: Nonsense-mediated decay.

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Journal Article•DOI•

Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function

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Olaf Isken¹, Lynne E. Maquat•Institutions (1)

University of Rochester¹

01 Aug 2007-Genes & Development

TL;DR: An overview of three quality control mechanisms--nonsense-mediated RNA decay, nonstop mRNA decay, and no-go mRNA decay--is provided, which surveys mRNAs during translation and degrades those m RNAs that direct aberrant protein synthesis.

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Abstract: Cells routinely make mistakes. Some mistakes are encoded by the genome and may manifest as inherited or acquired diseases. Other mistakes occur because metabolic processes can be intrinsically inefficient or inaccurate. Consequently, cells have developed mechanisms to minimize the damage that would result if mistakes went unchecked. Here, we provide an overview of three quality control mechanisms--nonsense-mediated mRNA decay, nonstop mRNA decay, and no-go mRNA decay. Each surveys mRNAs during translation and degrades those mRNAs that direct aberrant protein synthesis. Along with other types of quality control that occur during the complex processes of mRNA biogenesis, these mRNA surveillance mechanisms help to ensure the integrity of protein-encoding gene expression.

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593 citations

Cites background from "Applying nonsense-mediated mRNA dec..."

...Drug-mediated severing may provide a useful means to impair the NMD of particular disease-associated transcripts (Kuzmiak and Maquat 2006)....
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Journal Article•DOI•

hERG K+ Channels: Structure, Function, and Clinical Significance

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Jamie I. Vandenberg¹, Matthew D. Perry, Mark Perrin, Stefan A. Mann, Ying Ke, Adam P. Hill - Show less +2 more•Institutions (1)

Victor Chang Cardiac Research Institute¹

01 Jul 2012-Physiological Reviews

TL;DR: The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death.

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Abstract: The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

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565 citations

Cites background from "Applying nonsense-mediated mRNA dec..."

...A relative absence of truncated protein in the cell is likely the result of nonsense-mediated mRNA decay (344) (see sect....
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Journal Article•DOI•

Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene

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Manuel C. Lemos¹, Rajesh V. Thakker¹•Institutions (1)

University of Oxford¹

01 Jan 2008-Human Mutation

TL;DR: The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations, which are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.

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Abstract: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610–amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83–84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210–211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype–genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. Hum Mutat 29(1), 22–32, 2008. © 2007 Wiley-Liss, Inc.

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564 citations

Journal Article•DOI•

Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

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Maximilian W. Popp¹, Lynne E. Maquat¹•Institutions (1)

University of Rochester¹

25 Nov 2013-Annual Review of Genetics

TL;DR: Protein quality control is used as a conceptual framework to organize what is known about nonsense-mediated mRNA decay, highlighting overarching similarities between these two polymer quality control pathways, where the protein quality control and NMD pathways intersect, and howprotein quality control can suggest new avenues for research into mRNA quality control.

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Abstract: Cells use messenger RNAs (mRNAs) to ensure the accurate dissemination of genetic information encoded by DNA. Given that mRNAs largely direct the synthesis of a critical effector of cellular phenotype, i.e., proteins, tight regulation of both the quality and quantity of mRNA is a prerequisite for effective cellular homeostasis. Here, we review nonsense-mediated mRNA decay (NMD), which is the best-characterized posttranscriptional quality control mechanism that cells have evolved in their cytoplasm to ensure transcriptome fidelity. We use protein quality control as a conceptual framework to organize what is known about NMD, highlighting overarching similarities between these two polymer quality control pathways, where the protein quality control and NMD pathways intersect, and how protein quality control can suggest new avenues for research into mRNA quality control.

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349 citations

Journal Article•DOI•

Upf1 senses 3'UTR length to potentiate mRNA decay.

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J. Robert Hogg¹, J. Robert Hogg², Stephen P. Goff², Stephen P. Goff¹•Institutions (2)

Columbia University¹, Howard Hughes Medical Institute²

29 Oct 2010-Cell

TL;DR: It is demonstrated that Upf1 associates with mRNAs in a 3'UTR length-dependent manner and is highly enriched on transcripts containing3'UTRs known to elicit NMD, and proposed a model for 3'utR length surveillance in which equilibrium binding of Upf 1 to mRN as precedes a kinetically distinct commitment to RNA decay.

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331 citations

Cites background from "Applying nonsense-mediated mRNA dec..."

...Integrating the decision to decay over several termination events provides a mechanism to avoid degradation in response to translational errors while preserving the ability to recognize DNA- or RNA-encoded PTCs....
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...Transcripts preferentially targeted by NMD include those with PTCs encoded by alternatively splicedexons, intronsdownstreamof the termination codon (TC), long 30 untranslated regions (30UTRs), or upstream open reading frames (uORFs; reviewed in Nicholson et al., 2010; Rebbapragada and Lykke-Andersen, 2009)....
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...In addition to degrading transcripts containing premature termination codons (PTCs) resulting frommutation or rearrangement of genomic DNA or defects in mRNA biogenesis, the pathway is also responsible for regulating between 1% and 10% of all genes in diverse eukaryotes (He et al., 2003; Mendell et al., 2004; Rehwinkel et al., 2005; Wittmann et al., 2006; Weischenfeldt et al., 2008)....
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...Degradation of aberrant mRNAs by NMD can affect the progression of many human genetic disorders, an estimated one-third of which derive from PTCs (Kuzmiak and Maquat, 2006)....
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References

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Finishing the euchromatic sequence of the human genome

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Chris P. Ponting, Daniel Barker

21 Oct 2004-Nature

TL;DR: The current human genome sequence (Build 35) as discussed by the authors contains 2.85 billion nucleotides interrupted by only 341 gaps and is accurate to an error rate of approximately 1 event per 100,000 bases.

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Abstract: The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.

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Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.

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Jason M. Johnson¹, John C. Castle¹, Philip W. Garrett-engele¹, Zhengyan Kan¹, Patrick M. Loerch¹, Christopher D. Armour¹, Ralph Santos¹, Eric E. Schadt¹, Roland Stoughton¹, Daniel D. Shoemaker¹ - Show less +6 more•Institutions (1)

Merck & Co.¹

19 Dec 2003-Science

TL;DR: These genome-wide data provide experimental evidence and tissue distributions for thousands of known and novel alternative splicing events and indicate that at least 74% of human multi-exon genes are alternatively spliced.

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Abstract: Alternative pre-messenger RNA (pre-mRNA) splicing plays important roles in development, physiology, and disease, and more than half of human genes are alternatively spliced. To understand the biological roles and regulation of alternative splicing across different tissues and stages of development, systematic methods are needed. Here, we demonstrate the use of microarrays to monitor splicing at every exon-exon junction in more than 10,000 multi-exon human genes in 52 tissues and cell lines. These genome-wide data provide experimental evidence and tissue distributions for thousands of known and novel alternative splicing events. Adding to previous studies, the results indicate that at least 74% of human multi-exon genes are alternatively spliced.

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1,488 citations

"Applying nonsense-mediated mRNA dec..." refers background in this paper

...Considering that at least 74% of the estimated 20 000– 25 000 human genes undergo one or more alternative splicing events [ 22 ,23], NMD has the potential to contribute broadly to regulating proper gene expression by influencing the level of alternatively spliced transcripts....
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Journal Article•DOI•

A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance

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Eszter Nagy¹, Lynne E. Maquat¹•Institutions (1)

Roswell Park Cancer Institute¹

01 Jun 1998-Trends in Biochemical Sciences

TL;DR: This paper aims to explore the role of language and time in the development of romantic attachment and its role in the story of Henry IV.

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1,080 citations

"Applying nonsense-mediated mRNA dec..." refers background in this paper

...NMD can prevent autosomal recessive disease: how PTCs trigger NMD As a rule, only those PTCs that are located more than 50– 55 nucleotides upstream of a splicing-generated exon– exon junction within mRNA elicit NMD [ 25 ] (Figure 2). However, because there are exceptions to this rule [12,21,26], and exceptions are not usually predictable from mRNA sequence alone, it is advisable to confirm that an mRNA is an NMD target by quantitating the ......
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Journal Article•DOI•

From birth to death: the complex lives of eukaryotic mRNAs.

[...]

Melissa J. Moore¹•Institutions (1)

Howard Hughes Medical Institute¹

02 Sep 2005-Science

TL;DR: A comprehensive understanding of eukaryotic gene expression requires an appreciation for how the lives of mRNAs are influenced by a wide array of diverse regulatory mechanisms.

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Abstract: Recent work indicates that the posttranscriptional control of eukaryotic gene expression is much more elaborate and extensive than previously thought, with essentially every step of messenger RNA (mRNA) metabolism being subject to regulation in an mRNA-specific manner. Thus, a comprehensive understanding of eukaryotic gene expression requires an appreciation for how the lives of mRNAs are influenced by a wide array of diverse regulatory mechanisms.

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1,019 citations

"Applying nonsense-mediated mRNA dec..." refers background in this paper

...Instead, NMD is restricted to newly synthesized mRNAs that, in the case of most transcripts that have been examined, have yet to be released from an association with nuclei into the cytoplasm [ 2 ,12]....
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...In 88% of pre-mRNAs that derive from intron-containing genes [1], the introns are removed by a complex series of reactions that constitute the process of splicing [ 2 ] (Figure 1). Generally, introns begin with a 50-splice site (also called donor splice site) that has the canonical sequence 50-GU(A/ G)AGU-30, and end with a 30-splice site (also called acceptor splice site) that has the canonical sequence 50- (U/C)11N(C/U)AG-30....
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Journal Article•DOI•

Nonsense-Mediated mRNA Decay in Health and Disease

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Pamela A. Frischmeyer¹, Harry C. Dietz¹•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Jan 1999-Human Molecular Genetics

TL;DR: The current models of NMD that have been generated during the study of model organisms and mammalian cells are presented and the physiological burden of nonsense transcripts and the emerging view that NMD plays a broad and critical role in the regulation of gene expression are discussed.

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Abstract: All eukaryotes possess the ability to detect and degrade transcripts harboring premature signals for the termination of translation. Despite the ubiquitous nature of nonsense-mediated mRNA decay (NMD) and its demonstrated role in the modulation of phenotypes resulting from selected nonsense alleles, very little is known regarding its basic mechanism or the selective pressure for complete evolutionary conservation of this function. This review will present the current models of NMD that have been generated during the study of model organisms and mammalian cells. The physiological burden of nonsense transcripts and the emerging view that NMD plays a broad and critical role in the regulation of gene expression will also be discussed. Such issues are relevant to the proposal that pharmacological manipulation of NMD will find therapeutic application.

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976 citations

"Applying nonsense-mediated mRNA dec..." refers background in this paper

...Approximately 33% of inherited and acquired diseases are attributable to a premature termination codon (PTC), which truncates the ORF and precludes synthesis of fulllength protein [ 3 ]....
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