Control of Gene Expression Through the Nonsense-Mediated RNA Decay Pathway
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Nickless et al. Cell Biosci (2017) 7:26 DOI 10.1186/s13578-017-0153-7 Cell & Bioscience REVIEW Open Access Control of gene expression through the nonsense‑mediated RNA decay pathway Andrew Nickless1†, Julie M. Bailis2† and Zhongsheng You1* 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 stud- ies 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. Keywords: Nonsense-mediated decay, RNA surveillance, Gene expression, Human disease Background indirectly in certain cellular milieus [1, 10, 11]. Although Nonsense-mediated RNA decay (NMD) is an essential the overall process of NMD is conserved for both mutant RNA quality control and gene regulatory mechanism that and non-mutant transcripts, the signals that trigger is conserved among eukaryotes [1–9]. NMD safeguards NMD or its inhibition vary according to the specifc tar- the quality of the transcriptome and maintains cellular get and biological context. homeostasis by eliminating transcripts that harbor pre- In this review we focus on the function and impact of mature termination codons (PTCs). PTCs can arise from NMD on normal gene expression in mammals. We out- errors in nucleic acid metabolism, such as genetic muta- line the NMD process and highlight the known roles for tions or defects in splicing or transcription. In addition, NMD in normal physiology, with a particular emphasis PTCs may also form during mRNA synthesis from nor- on its function as a gene regulatory mechanism and its mal gene structures, including from programmed recom- dynamic regulation by environmental and developmental bination. In its canonical role, NMD prevents translation signals. We conclude with an overview of the impact of of transcripts that might produce C-terminally truncated NMD dysregulation on human disease and discuss the proteins with reduced or aberrant function. potential of treating genetic and neurological disorders NMD also targets non-mutant transcripts, and its and cancer by manipulating NMD activity. regulation of normal gene expression impacts a wide range of physiological processes including cell diferen- Overview of the NMD pathway tiation, response to stress and development of disease. First discovered in yeast and then extensively studied in Recent estimates suggest that NMD-mediated degrada- Caenorhabditis elegans, Drosophila, mouse, human cells, tion afects up to 25% of transcripts, either directly or and other model systems, NMD is a RNA surveillance pathway that acts at the interface between transcrip- tion and translation [10, 12–15]. NMD must accurately *Correspondence: [email protected] †Andrew Nickless and Julie M. Bailis contributed equally to this work distinguish a PTC from a normal stop codon on an 1 Department of Cell Biology & Physiology, Washington University School mRNA and then recruit and activate enzymes to destroy of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, the transcript. Tere are two main models to explain USA Full list of author information is available at the end of the article how transcripts are identifed as targets for NMD. Te © The Author(s) 2017. This 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. Nickless et al. Cell Biosci (2017) 7:26 Page 2 of 12 exon-junction complex (EJC) model proposes that data are possible, including the possibility that NMD EJC—a large multi-protein assembly deposited ~20–24 occurs during nuclear export, of which there is some bases upstream of an exon–exon junction as a result of evidence [66]. pre-mRNA splicing—acts as a second signal to mark an upstream stop codon as a PTC [16–29]. During transla- Role of NMD and its regulation in normal tion, ribosomes scan the mRNA and will pause at a stop physiological processes codon. If an EJC is present more than 50–55 bases down- Bioinformatics analysis of EST databases and RNA stream of the stop codon, the protein kinase SMG1, its sequencing data in cells where NMD is disrupted have substrate Upf1, a ATPase/helicase, and eukaryotic poly- clearly demonstrated that NMD has a widespread efect peptide release factors eRF1 and eRF3 are then recruited on gene expression [10, 67, 68]. Tis realization has led to form a complex—the SURF complex—on the mRNA. to the identifcation of numerous putative NMD target Phosphorylation of UPF1 by SMG1 leads to the recruit- mRNAs, based on characteristics such as PTCs or long ment of SMG5, SMG6 and SMG7 via phospho-specifc 3′ UTRs and an observed increase in the stability and/or interactions [30, 31]. After recruitment, SMG5 and levels of transcripts after NMD suppression [1, 4, 5, 11, SMG7 promote RNA decapping and deadenylation by 69–75]. recruiting factors such as DCP1a and POP2, leading to Multiple mechanisms exist to generate PTCs in tran- the exposure of the transcript ends to cellular exonucle- scripts of normal genes (Fig. 1). Alternative splicing gen- ases [32–39]. SMG6, which has endonuclease activity, erates diversity in mRNA isoforms but can also lead to provides a second mechanism for initiation of mRNA formation of PTCs that target transcripts for NMD. For decay by cleaving transcripts internally near the PTC, instance, the RNA binding protein polypyrimidine tract generating two unprotected RNA ends that are further binding protein 1 (PTBP1) can repress splicing of exon 11 degraded by cellular nucleases [40–43]. of its own mRNA, leading to NMD of the transcript [76]. Te second model for NMD posits that the abnormally As such, PTBP1 negatively regulates its own expression. long 3′ untranslated region (UTR) downstream of a PTC Human arginine–serine rich (SR) splicing factors have acts as a second signal to promote PTC recognition. also been shown to be regulated by alternative splicing While the molecular mechanism of this model is less well coupled to NMD [77, 78]. Tis so-called unproductive defned, it has been proposed that accumulation of UPF1 splicing and translation (RUST) represents an autoregu- as well as other regulatory elements in the 3′ UTR medi- latory mechanism that controls the levels of splicing fac- ates the recruitment of other NMD factors and the initia- tors and other RNA binding proteins [77–81]. Te use of tion of mRNA decay [44–47]. For additional information alternative transcription initiation sites can also generate about the mechanisms of PTC recognition, readers are mRNA isoforms with a stop codon upstream of a splice directed to a number of recent reviews [13, 48–50]. junction, resulting in NMD [82]. Programmed ribosomal A debate remains about where NMD takes place in frameshifting (PRF)—which can potentially occur in up the cell. NMD inherently relies on the translation pro- to 8–12% of genes—is another mechanism that can cre- cess, which normally occurs in the cytoplasm. However, ate a PTC, leading to NMD [83–86]. Stop codons that some investigators have proposed that translation can trigger NMD can also form if the primary coding region also take place in the cell nucleus [51–53]. Several stud- of an mRNA is preceded by an upstream open reading ies suggest that NMD is associated with the nucleus or frame (uORF) [87, 88]. Transcriptome analysis indicates nuclear fraction. For example, levels of PTC-contain- that long 3′ UTRs are among the most common features ing triosephosphate isomerase (TPI) and mouse major of NMD targets, although 3′ UTR length per se is not urinary protein (MUP) transcripts were specifcally considered a reliable predictor of NMD of a given tran- reduced in the nuclear fraction [54–57]. NMD-medi- script [29, 44–46, 74, 88–91]. ated degradation of the TCRβ transcript can also take Transcripts encoding selenoproteins comprise another place in purifed nuclei [58]. Several other nonsense interesting class of NMD targets. A UGA codon normally reporter mRNAs also appear to be targeted by NMD in signals a stop to translation but can be redefned to code the nucleus [51, 59–64]. Te idea of PTC recognition in for the amino acid selenocysteine in a high selenium the nucleus is also consistent with the existence of non- environment [92]. If selenocysteine is incorporated in the sense-associated altered splicing (NAS), a NMD-related last exon of a transcript it generally evades NMD, while nuclear pathway that also requires PTC recognition if selenium is not abundant, these transcripts will be [65]. However, the claims of nuclear NMD and transla- degraded via NMD if their stop codon resides upstream tion remain controversial as other lines of evidence sug- of an exon–exon junction [93, 94]. Tis regulatory mech- gest that NMD is primarily a cytoplasmic process [25]. anism enables cells to respond to alterations in levels of Indeed, alternative interpretations of the nuclear NMD the essential trace element selenium. Terefore, while Nickless et al. Cell Biosci (2017) 7:26 Page 3 of 12 NMD Regulation of RNA Quality Control Gene Expression Aberrant Transcripts Normal Transcripts Genetic uORF Mutations Alternative PTC Aberrant Splicing Splicing No PTC Inaccurate Transcription Intron Programmed Ribosomal Frameshifting Frameshifting Signal Fig.