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F1000 Biol Rep. 2009; 1: 93.
Published online 2009 December 9. doi:  10.3410/B1-93
PMCID: PMC2948277

Aberrant mRNA transcripts and nonsense-mediated decay


Nobody's perfect, and even the cell turns out a certain fraction of erroneous mRNA transcripts. One of the key quality control mechanisms put in place to recognize and eliminate these transcripts before they can be translated into faulty proteins is nonsense-mediated decay. Proteins involved in nonsense-mediated decay are highly conserved across species from plants to humans, and recent studies in Arabidopsis thaliana reveal both intriguing similarities and differences in the mechanisms employed to carry it out.

Introduction and context

RNA surveillance pathways scan for errors arising during transcription and splicing, targeting aberrant RNAs for degradation [1]. Nonsense-mediated decay (NMD) is one such pathway, detecting mRNAs that harbor premature termination or ‘nonsense’ codons (PTCs) [2,3]. It has been estimated that NMD regulates approximately 10% of all human mRNAs, and that approximately 30% of all disease-associated mutations generate PTCs. The core machinery comprises three trans-acting factors called up-frameshift (UPF) proteins. UPF1 is an RNA helicase recruited to mRNAs upon recognition of stop codons by the translation apparatus. Rapid decay is triggered when UPF1 interacts with UPF2 and UPF3. A key event linking recognition of PTCs to NMD is phosphorylation of UPF1 by the SMG1 kinase and recruitment of the translational termination release factors eRF1 and eRF3 (to form the SURF complex), which promotes transcriptional repression and recruitment of mRNA degradation proteins [4].

In yeast and invertebrates, abnormally long 3′ untranslated regions (UTRs) downstream of stop codons can act as signals for NMD, while in mammalian cells it is primarily the location of the exon junction complex (EJC) [2]. This multiprotein complex is deposited 20-24 nucleotides upstream of exon-exon junctions after pre-mRNA splicing. By marking the location of introns relative to the stop codon, the EJC can signal the presence of a PTC and recruit NMD factors that target the transcript for decay.

Until recently, plant NMD was poorly understood, although many of the protein factors involved in NMD in other eukaryotes were known to be present. Surprisingly, proteomic analysis of purified Arabidopsis nucleoli placed six components of the EJC within this subnuclear organelle [5,6]. The nucleolus, best known as the site of ribosome biogenesis, has recently been implicated in a much wider range of functions, including regulation of mitosis, stress response, biogenesis of ribonucleoprotein particles, RNA editing, and processing of non-coding RNAs [7,8]. The presence of EJC proteins in both the Arabidopsis [5] and human [9] nucleolar proteome suggests that this structure may have additional functions in mRNA export and NMD-mediated mRNA surveillance. Yeast nucleoli have long been implicated in processing and transport of poly(A)+ mRNA [10]. As illustrated in Figure 1, plant nucleoli and nucleolar-associated Cajal and D-bodies have also been implicated as sites of small interfering RNA and microRNA biogenesis [11-15], and several recent studies have detected microRNA-like small non-coding RNAs derived from small nucleolar RNAs in mammals, protozoans, and viruses [16-19]. It is not that far-reaching to suggest that, once the nucleolus evolved as a site enriched in rRNA processing proteins, the cell subsequently exploited it as a convenient site to carry out other RNA processing functions.

Figure 1.
RNA processing in the Arabidopsis nucleus

Major recent advances

Plant nonsense-mediated decay pathways

When plant NMD was first analyzed to determine whether it uses a system more like that found in yeast or in mammalian cells, the unexpected answer was ‘both’ [20-22]. Recently, Kerényi et al. [23] undertook a functional dissection of these pathways in Nicotiana benthamiana and identified several of the trans factors involved. They verified the co-existence of two NMD pathways: one that eliminates mRNAs with long 3′ UTRs in a manner similar to yeast NMD and a second, distinct pathway that degrades mRNAs harboring 3′ UTR-located introns. The EJC factors Mago and Y14 were shown to only be required for this intron-based pathway, suggesting that it is similar to mammalian NMD. In addition, a protein involved in both pathways, SMG7, was found to be subject to feedback regulation, suggesting the evolutionary conservation of NMD autoregulation throughout all eukaryotes.

Enrichment of aberrant mRNA and NMD proteins in plant nucleoli

With the exact location(s) of NMD in mammalian cells still under debate, particularly with regard to the identification and labeling of PTC+ transcripts, recent results from Arabidopsis studies raise the intriguing possibility that certain steps in the plant NMD pathway may occur, at least in part, within the nucleus. Having previously shown the association of EJC and NMD proteins with the plant nucleolus using a proteomic approach [5], Kim et al. [24] next compared the distribution of mRNA classes in whole cell, nuclear, and nucleolar libraries. Not only did they show that mRNAs are present in nucleoli, they demonstrated a clear abundance of aberrantly-spliced mRNAs in this structure compared with the nucleoplasm. Further examination of these transcripts revealed that most contain PTCs and are putative or known targets of NMD, and several were shown to accumulate in NMD-mutant plants, suggesting a correlation between the enrichment of aberrant mRNAs in nucleoli and their turnover by NMD.

In addition to EJC proteins and aberrant mRNAs, NMD factors UPF2 and UPF3 were also shown to localize to the plant nucleolus. However, while plant UPF3 shows a clear accumulation in nucleoli, human UPF3, although detected in the nucleolar proteome [9], is predominantly nucleoplasmic. This difference is surprising, and may indicate a unique function for the nucleolus in plant NMD. UPF1 is primarily cytoplasmic in both species. One possibility put forth by the authors is that plants identify intron-containing transcripts and prepare them for degradation by the NMD pathway in the nucleus and nucleolus, while other PTC+ transcripts without intron fragments are identified upon export by a pioneer round of translation.

Future directions

These studies highlight the importance of considering eukaryotic pathways in their evolutionary context. The two NMD pathways described here to identify and target specific classes of aberrant mRNA for degradation in plant cells bear striking similarities to counterpart systems in yeast and mammals. At the same time, the obligatory role of splicing and the EJC in initiating NMD in mammalian cells is being questioned, with alternative or complementary EJC-independent pathways proposed [25,26]. Taken together, the results suggest that these RNA surveillance pathways may be more evolutionarily conserved than previously thought, despite the apparent simplification in certain lineages.

Although the presence of NMD factors in the nucleolus suggests a role in this pathway, several questions remain. For example, it is still unclear how aberrant transcripts are recognized and targeted to the nucleolus, and whether NMD can occur in the nucleus or relies on the transfer of aberrant mRNPs to the cytoplasm. Indeed, controversy still exists over the location of EJC-mediated NMD in mammalian cells. While it is generally agreed that a pioneering round of translation is required to detect a PTC, and the current consensus is that this initial round of translation occurs in the cytoplasm, in close proximity to the nucleus [27,28], the possibility of some sort of proofreading or downstream processing step in the nucleus cannot be ruled out. It is likely that dissection of NMD pathways in eukaryotic systems will continue to throw up surprises.


exon-joining complex
nonsense-mediated decay
premature termination codon
untranslated region


The electronic version of this article is the complete one and can be found at:


Competing interests

The author declares that she has no competing interests.


1. Houseley J, Tollervey D. The many pathways of RNA degradation. Cell. 2009;136:763–76. doi: 10.1016/j.cell.2009.01.019. [PubMed] [Cross Ref]
2. Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007;76:51–74. doi: 10.1146/annurev.biochem.76.050106.093909. [PubMed] [Cross Ref]
3. Stalder L, Mühlemann O. The meaning of nonsense. Trends Cell Biol. 2008;18:315–21. doi: 10.1016/j.tcb.2008.04.005. [PubMed] [Cross Ref]
4. Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev. 2006;20:355–67. doi: 10.1101/gad.1389006. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Lynne Maquat 08 Feb 2006
5. Pendle AF, Clark GP, Boon R, Lewandowska D, Lam YW, Andersen J, Mann M, Lamond AI, Brown JW, Shaw PJ. Proteomic analysis of the Arabidopsis nucleolus suggests novel nucleolar functions. Mol Biol Cell. 2005;16:260–9. doi: 10.1091/mbc.E04-09-0791. [PMC free article] [PubMed] [Cross Ref]
6. Brown JW, Shaw PJ, Shaw P, Marshall DF. Arabidopsis nucleolar protein database (AtNoPDB) Nucleic Acids Res. 2005;33:D633-6. doi: 10.1093/nar/gki052. [PMC free article] [PubMed] [Cross Ref]
7. Boisvert FM, van Koningsbruggen S, Navascués J, Lamond AI. The multifunctional nucleolus. Nat Rev Mol Cell Biol. 2007;8:574–85. doi: 10.1038/nrm2184. [PubMed] [Cross Ref]
8. Pederson T. The plurifunctional nucleolus. Nucleic Acids Res. 1998;26:3871–6. doi: 10.1093/nar/26.17.3871. [PMC free article] [PubMed] [Cross Ref]
9. Ahmad Y, Boisvert FM, Gregor P, Cobley A, Lamond AI. NOPdb: Nucleolar Proteome Database--2008 update. Nucleic Acids Res. 2009;37:D181-4. doi: 10.1093/nar/gkn804. [PMC free article] [PubMed] [Cross Ref]
10. Schneiter R, Kadowaki T, Tartakoff AM. mRNA transport in yeast: time to reinvestigate the functions of the nucleus. Mol Biol Cell. 1995;6:357–70. [PMC free article] [PubMed]
11. Fang Y, Spector DL. Identification of nuclear dicing bodies containing proteins for microRNA biogenesis in living Arabidopsis plants. Curr Biol. 2007;17:818–23. doi: 10.1016/j.cub.2007.04.005. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 3.2 Recommended
Evaluated by Julia Kehr 16 May 2007, Craig Pikaard 27 Jun 2007
12. Li CF, Pontes O, El-Shami M, Henderson IR, Bernatavichute YV, Chan SW, Lagrange T, Pikaard CS, Jacobsen SE. An ARGONAUTE4-containing nuclear processing center colocalized with Cajal bodies in Arabidopsis thaliana. Cell. 2006;126:93–106. doi: 10.1016/j.cell.2006.05.032. [PubMed] [Cross Ref] F1000 Factor 8.0 Exceptional
Evaluated by James Carrington 08 Aug 2006, Edouard Bertrand 02 Jan 2007
13. Pontes O, Li CF, Nunes PC, Haag J, Ream T, Vitins A, Jacobsen SE, Pikaard CS. The Arabidopsis chromatin-modifying nuclear siRNA pathway involves a nucleolar RNA processing center. Cell. 2006;126:79–92. doi: 10.1016/j.cell.2006.05.031. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by James Carrington 08 Aug 2006
14. Fujioka Y, Utsumi M, Ohba Y, Watanabe Y. Location of a possible miRNA processing site in SmD3/SmB nuclear bodies in Arabidopsis. Plant Cell Physiol. 2007;48:1243–53. doi: 10.1093/pcp/pcm099. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Craig Pikaard 06 Nov 2007
15. Song L, Han MH, Lesicka J, Fedoroff N. Arabidopsis primary microRNA processing proteins HYL1 and DCL1 define a nuclear body distinct from the Cajal body. Proc Natl Acad Sci U S A. 2007;104:5437–42. doi: 10.1073/pnas.0701061104. [PubMed] [Cross Ref]
16. Ender C, Krek A, Friedländer MR, Beitzinger M, Weinmann L, Chen W, Pfeffer S, Rajewsky N, Meister G. A human snoRNA with microRNA-like functions. Mol Cell. 2008;32:519–28. doi: 10.1016/j.molcel.2008.10.017. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Upinder Singh 09 Dec 2008
17. Politz JC, Hogan EM, Pederson T. MicroRNAs with a nucleolar location. RNA. 2009;15:1705–15. doi: 10.1261/rna.1470409. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Peter Shaw 15 Oct 2009
18. Saraiya AA, Wang CC. snoRNA, a novel precursor of microRNA in Giardia lamblia. PLoS Pathog. 2008;4:e1000224. doi: 10.1371/journal.ppat.1000224. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Upinder Singh 12 Dec 2008
19. Hutzinger R, Feederle R, Mrazek J, Schiefermeier N, Balwierz PJ, Zavolan M, Polacek N, Delecluse HJ, Hüttenhofer A. Expression and processing of a small nucleolar RNA from the Epstein-Barr virus genome. PLoS Pathog. 2009;5:e1000547. doi: 10.1371/journal.ppat.1000547. [PMC free article] [PubMed] [Cross Ref]
20. Kertész S, Kerényi Z, Mérai Z, Bartos I, Pálfy T, Barta E, Silhavy D. Both introns and long 3′-UTRs operate as cis-acting elements to trigger nonsense-mediated decay in plants. Nucleic Acids Res. 2006;34:6147–57. doi: 10.1093/nar/gkl737. [PMC free article] [PubMed] [Cross Ref]
21. Hori K, Watanabe Y. Context analysis of termination codons in mRNA that are recognized by plant NMD. Plant Cell Physiol. 2007;48:1072–8. doi: 10.1093/pcp/pcm075. [PubMed] [Cross Ref]
22. Wu J, Kang JH, Hettenhausen C, Baldwin IT. Nonsense-mediated mRNA decay (NMD) silences the accumulation of aberrant trypsin proteinase inhibitor mRNA in Nicotiana attenuata. Plant J. 2007;51:693–706. doi: 10.1111/j.1365-313X.2007.03173.x. [PubMed] [Cross Ref]
23. Kerényi Z, Mérai Z, Hiripi L, Benkovics A, Gyula P, Lacomme C, Barta E, Nagy F, Silhavy D. Inter-kingdom conservation of mechanism of nonsense-mediated mRNA decay. EMBO J. 2008;27:1585–95. doi: 10.1038/emboj.2008.88. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Laura Trinkle-Mulcahy 27 Nov 2009
24. Kim SH, Koroleva OA, Lewandowska D, Pendle AF, Clark GP, Simpson CG, Shaw PJ, Brown JW. Aberrant mRNA transcripts and the nonsense-mediated decay proteins UPF2 and UPF3 are enriched in the Arabidopsis nucleolus. Plant Cell. 2009;21:2045–57. doi: 10.1105/tpc.109.067736. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Laura Trinkle-Mulcahy 27 Nov 2009
25. Bühler M, Steiner S, Mohn F, Paillusson A, Mühlemann O. EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3′ UTR length. Nat Struct Mol Biol. 2006;13:462–4. doi: 10.1038/nsmb1081. [PubMed] [Cross Ref]
26. Brogna S, Wen J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol. 2009;16:107–13. doi: 10.1038/nsmb.1550. [PubMed] [Cross Ref]
27. Bhalla AD, Gudikote JP, Wang J, Chan WK, Chang YF, Olivas OR, Wilkinson MF. Nonsense codons trigger an RNA partitioning shift. J Biol Chem. 2009;284:4062–72. doi: 10.1074/jbc.M805193200. [PubMed] [Cross Ref]
28. Sato H, Hosoda N, Maquat LE. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol Cell. 2008;29:255–62. doi: 10.1016/j.molcel.2007.12.009. [PubMed] [Cross Ref]

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