Key Points
-
Cytoplasmic mRNA decay constitutes an important post-transcriptional mechanism in mammalian cells that, together with gene transcription, precursor mRNA (pre-mRNA) processing and mRNA transport mechanisms, regulates the ultimate level of protein-encoding gene expression.
-
The regulation of cytoplasmic mRNA half-life is mediated by mRNA-binding proteins and non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs. The level and/or activity of mRNA-binding proteins can vary depending on their post-translational modifications, which can differ between different cell types or changes in cell signalling within a particular cell type; the level and/or activity of ncRNAs can be regulated by the efficiency of their formation.
-
The regulation of cytoplasmic mRNA half-life can also be affected by the translational status of the mRNA. Translation can remove regulatory proteins or ncRNAs from mRNAs should they associate with mRNA coding regions.
-
Some mechanisms of mRNA decay largely maintain the quality of gene expression, as exemplified by nonsense-mediated mRNA decay (NMD). NMD generally degrades newly synthesized mRNAs, depending on where translation terminates, and it is regulated as a means of maintaining cellular homeostasis.
-
Genes encoding protein products that contribute to a distinct phase (or phases) of the cell cycle are often regulated at the level of mRNA half-life as well as the level of transcription. An example of this is provided by metazoan histone genes, whose mRNAs that are degraded at the end of S phase when DNA synthesis is completed and there is no further need for histone protein synthesis.
-
mRNA decay is a target of numerous signal transduction pathways. Site-specific phosphorylation controls the subcellular distribution of stabilizing and destabilizing proteins and their ability to interact with degradative enzymes to activate decay.
-
Nuclear receptors can have a dual function in activating decay, by inducing the expression of one or more destabilizing proteins or by binding directly to mRNAs to activate their degradation.
-
The AU-rich elements (AREs) are the largest group of cis-acting elements controlling mRNA decay. Destabilizing ARE-binding proteins function primarily by recruiting enzymes that catalyse shortening of the poly(A) tail, and ARE-containing mRNAs are stabilized by modifications (for example, by phosphorylation) that block the recruitment of deadenylases or by competitive binding of stabilizing ARE-binding proteins.
-
Some of the enzymes that catalyse mRNA decay are themselves targets for regulation. To date, these are all endonucleases, and they are either induced in response to a particular stimulus or their enzymatic activity is increased in response to stress or to a particular stimulus.
Abstract
Discoveries made over the past 20 years highlight the importance of mRNA decay as a means of modulating gene expression and thereby protein production. Up until recently, studies largely focused on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay and the ribonucleases that catalyse decay. Now, current studies have begun to elucidate how the decay process is regulated. This Review examines our current understanding of how mammalian cell mRNA decay is controlled by different signalling pathways and lays out a framework for future research.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
09 May 2012
In panel a of the figure in Box 1 of this article, the labels for the exonuclease activities were reversed. The figure has now been corrected. The editors apologize for this error.
References
Moore, M. J. & Proudfoot, N. J. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688–700 (2009).
Chen, C. Y. & Shyu, A. B. Mechanisms of deadenylation-dependent decay. Wiley Interdisc. Rev. RNA 2, 167–183 (2010).
Li, Y. & Kiledjian, M. Regulation of mRNA decapping. Wiley Interdiscip. Rev. RNA 1, 253–265 (2010).
Schoenberg, D. R. Mechanisms of endonuclease-mediated mRNA decay. Wiley Interdisc. Rev. RNA 2, 582–600 (2011).
Maquat, L. E., Tarn, W. Y. & Isken, O. The pioneer round of translation: features and functions. Cell 142, 368–374 (2010).
Mendell, J. T., Sharifi, N. A., Meyers, J. L., Martinez-Murillo, F. & Dietz, H. C. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature Genet. 36, 1073–1078 (2004).
Wittmann, J., Hol, E. M. & Jack, H. M. hUPF2 silencing identifies physiologic substrates of mammalian nonsense-mediated mRNA decay. Mol. Cell. Biol. 26, 1272–1287 (2006).
Apcher, S. et al. Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. Proc. Natl Acad. Sci. USA 108, 11572–11577 (2011).
Ghosh, S. & Jacobson, A. RNA decay modulates gene expression and controls its fidelity. Wiley Interdisc. Rev. RNA 1, 351–361 (2010).
Nicholson, P. & Muhlemann, O. Cutting the nonsense: the degradation of PTC-containing mRNAs. Biochem. Soc. Trans. 38, 1615–1620 (2010).
Hwang, J., Sato, H., Tang, Y., Matsuda, D. & Maquat, L. E. UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps. Mol. Cell 39, 396–409 (2010). This paper provided mechanistic rationale for why NMD in mammalian cells appears to be restricted to CBC-bound mRNA.
Wang, D., Wengrod, J. & Gardner, L. B. Overexpression of the c-myc oncogene inhibits nonsense-mediated RNA decay in B lymphocytes. J. Biol. Chem. 286, 40038–40043 (2011).
Wang, D. et al. Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol. Cell. Biol. 31, 3670–3680 (2011).
Cam, H., Easton, J. B., High, A. & Houghton, P. J. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol. Cell 40, 509–520 (2010).
Gardner, L. B. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol. Cell. Biol. 28, 3729–3741 (2008).
Lee, H. C., Choe, J., Chi, S. G. & Kim, Y. K. Exon junction complex enhances translation of spliced mRNAs at multiple steps. Biochem. Biophys. Res. Commun. 384, 334–340 (2009).
Diem, M. D., Chan, C. C., Younis, I. & Dreyfuss, G. PYM binds the cytoplasmic exon-junction complex and ribosomes to enhance translation of spliced mRNAs. Nature Struct. Mol. Biol. 14, 1173–1179 (2007).
Sato, H., Hosoda, N. & Maquat, L. E. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol. Cell 29, 255–262 (2008).
Michlewski, G., Sanford, J. R. & Caceres, J. F. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol. Cell 30, 179–189 (2008).
Richardson, C. J. et al. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr. Biol. 14, 1540–1549 (2004).
Matsuda, D., Hosoda, N., Kim, Y. K. & Maquat, L. E. Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nature Struct. Mol. Biol. 14, 974–979 (2007).
Eberle, A. B., Stalder, L., Mathys, H., Orozco, R. Z. & Muhlemann, O. Posttranscriptional gene regulation by spatial rearrangement of the 3′ untranslated region. PLoS Biol. 6, e92 (2008).
Isken, O. et al. Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay. Cell 133, 314–327 (2008).
Okada-Katsuhata, Y. et al. N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD. Nucleic Acids Res. 40, 1251–1266 (2012).
Kashima, I. et al. 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. 20, 355–367 (2006).
Ohnishi, T. et al. Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Mol. Cell 12, 1187–1200 (2003).
Chan, W. K. et al. A UPF3-mediated regulatory switch that maintains RNA surveillance. Nature Struct. Mol. Biol. 16, 747–753 (2009).
Yepiskoposyan, H., Aeschimann, F., Nilsson, D., Okoniewski, M. & Muhlemann, O. Autoregulation of the nonsense-mediated mRNA decay pathway in human cells. RNA 17, 2108–2118 (2011).
Huang, L. et al. RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD. Mol. Cell 43, 950–961 (2011). This study provided the first evidence for the feedback regulation of NMD by rate-limiting NMD factors as a means to maintain cellular homeostasis.
Choe, J., Cho, H., Lee, H. C. & Kim, Y. K. microRNA/Argonaute 2 regulates nonsense-mediated messenger RNA decay. EMBO Rep. 11, 380–386 (2010).
Linde, L., Boelz, S., Neu-Yilik, G., Kulozik, A. E. & Kerem, B. The efficiency of nonsense-mediated mRNA decay is an inherent character and varies among different cells. Eur. J. Hum. Genet. 15, 1156–1162 (2007).
Gong, C., Kim, Y. K., Woeller, C. F., Tang, Y. & Maquat, L. E. SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs. Genes Dev. 23, 54–66 (2009).
Bruno, I. G. et al. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol. Cell 42, 500–510 (2011). This paper presented evidence for a mechanistic link between the brain-specific miR-128-mediated pathway and NMD. This link appears to be conserved among diverse species as a means of controlling neuron development and activity.
Hwang, J. & Maquat, L. E. Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question. Curr. Opin. Genet. Dev. 21, 422–430 (2011).
Marzluff, W. F., Wagner, E. J. & Duronio, R. J. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nature Rev. Genet. 9, 843–854 (2008).
Kaygun, H. & Marzluff, W. F. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1. Nature Struct. Mol. Biol. 12, 794–800 (2005).
Zheng, L. et al. Phosphorylation of stem–loop binding protein (SLBP) on two threonines triggers degradation of SLBP, the sole cell cycle-regulated factor required for regulation of histone mRNA processing, at the end of S phase. Mol. Cell. Biol. 23, 1590–1601 (2003).
Koseoglu, M. M., Dong, J. & Marzluff, W. F. Coordinate regulation of histone mRNA metabolism and DNA replication: cyclin A/cdk1 is involved in inactivation of histone mRNA metabolism and DNA replication at the end of S phase. Cell Cycle 9, 3857–3863 (2010).
Martin, A. N. & Li, Y. RNase MRP RNA and human genetic diseases. Cell Res. 17, 219–226 (2007).
Bakheet, T., Williams, B. R. & Khabar, K. S. ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Res. 34, D111–D114 (2006).
Chen, C. Y. & Shyu, A. B. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem. Sci. 20, 465–470 (1995).
Yamashita, A. et al. Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover. Nature Struct. Mol. Biol. 12, 1054–1063 (2005).
Murray, E. L. & Schoenberg, D. R. A+U-rich instability elements differentially activate 5′-3′ and 3′-5′ mRNA decay. Mol. Cell. Biol. 27, 2791–2799 (2007).
Vlasova-St. Louis, I. & Bohjanen, P. R. Coordinate regulation of mRNA decay networks by GU-rich elements and CELF1. Curr. Opin. Genet. Dev. 4, 444–451 (2011).
Beisang, D., Rattenbacher, B., Vlasova-St Louis, I. A. & Bohjanen, P. R. Regulation of CUG-binding protein 1 (CUGBP1) binding to target transcripts upon T cell activation. J. Biol. Chem. 287, 950–960 (2012).
Zhang, L., Lee, J. E., Wilusz, J. & Wilusz, C. J. The RNA-binding protein CUGBP1 regulates stability of tumor necrosis factor mRNA in muscle cells: implications for myotonic dystrophy. J. Biol. Chem. 283, 22457–22463 (2008).
Dasgupta, T. & Ladd, A. N. The importance of CELF control: molecular and biologcial roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdiscip. Rev. RNA 3, 104–121 (2012).
Abdelmohsen, K. & Gorospe, M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip. Rev. RNA 1, 214–229 (2010).
von Roretz, C., Di Marco, S., Mazroui, R. & Gallouzi, I. E. Turnover of AU-rich-containing mRNAs during stress: a matter of survival. Wiley Interdiscip. Rev. RNA 2, 336–347 (2011).
Gratacos, F. M. & Brewer, G. The role of AUF1 in regulated mRNA decay. Wiley Interdiscip. Rev. RNA 1, 457–473 (2010).
Sanduja, S., Blanco, F. F. & Dixon, D. A. The roles of TTP and BRF proteins in regulated mRNA decay. Wiley Interdiscip. Rev. RNA 2, 42–57 (2011).
Schott, J. & Stoecklin, G. Networks controlling mRNA decay in the immune system. Wiley Interdiscip. Rev. RNA 1, 432–456 (2010).
Eberhardt, W., Doller, A., Akool, El-S. & Pfeilschifter, J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol. Ther. 114, 56–73 (2007).
Raghavan, A. et al. Patterns of coordinate down-regulation of ARE-containing transcripts following immune cell activation. Genomics 84, 1002–1013 (2004).
Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009).
Lykke-Andersen, J. & Wagner, E. Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev. 19, 351–361 (2005).
Mahtani, K. R. et al. Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor α mRNA stability. Mol. Cell. Biol. 21, 6461–6469 (2001).
Chrestensen, C. A. et al. MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J. Biol. Chem. 279, 10176–10184 (2004).
Stoecklin, G. et al. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 23, 1313–1324 (2004).
Hitti, E. et al. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol. Cell. Biol. 26, 2399–2407 (2006).
Marchese, F. P. et al. MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J. Biol. Chem. 285, 27590–27600 (2010).
Clement, S. L., Scheckel, C., Stoecklin, G. & Lykke-Andersen, J. Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol. Cell. Biol. 31, 256–266 (2011).
Maitra, S. et al. The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase-activated protein kinase 2. RNA 14, 950–959 (2008).
Schmidlin, M. et al. The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J. 23, 4760–4769 (2004).
Graham, J. R., Hendershott, M. C., Terragni, J. & Cooper, G. M. mRNA degradation plays a significant role in the program of gene expression regulated by phosphatidylinositol 3-kinase signaling. Mol. Cell. Biol. 30, 5295–5305 (2010).
Briata, P. et al. p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Mol. Cell 20, 891–903 (2005).
Winzen, R. et al. Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets. Mol. Cell. Biol. 27, 8388–8400 (2007).
Wilson, G. M. et al. Regulation of A + U-rich element-directed mRNA turnover involving reversible phosphorylation of AUF1. J. Biol. Chem. 278, 33029–33038 (2003).
Fawal, M. et al. A “liaison dangereuse” between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK. Blood 108, 2780–2788 (2006).
Sun, L. et al. Tristetraprolin (TTP)–14-3-3 complex formation protects TTP from dephosphorylation by protein phosphatase 2a and stabilizes tumor necrosis factor-α mRNA. J. Biol. Chem. 282, 3766–3777 (2007).
Lee, W. H. et al. Casein kinase 2 regulates the mRNA-destabilizing activity of tristetraprolin. J. Biol. Chem. 286, 21577–21587 (2011).
Brook, M. et al. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol. Cell. Biol. 26, 2408–2418 (2006).
Yu, H., Sun, Y., Haycraft, C., Palanisamy, V. & Kirkwood, K. L. MKP-1 regulates cytokine mRNA stability through selectively modulation subcellular translocation of AUF1. Cytokine 56, 245–255 (2011).
Kim, H. H. et al. Nuclear HuR accumulation through phosphorylation by Cdk1. Genes Dev. 22, 1804–1815 (2008). This is a detailed analysis of nucleocytoplasmic partitioning of HuR as a function of site-specific phosphorylation during the cell cycle.
Doller, A. et al. Protein kinase C α-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2. Mol. Biol. Cell 18, 2137–2148 (2007).
Doller, A. et al. Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cδ elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol. Cell. Biol. 28, 2608–2625 (2008).
Lafarga, V. et al. p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21Cip1 mRNA mediates the G1/S checkpoint. Mol. Cell. Biol. 29, 4341–4351 (2009).
Li, H. et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J. Biol. Chem. 277, 44623–44630 (2002).
Mukherjee, N. et al. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol. Cell 43, 327–339 (2011).
Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I. & Filipowicz, W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111–1124 (2006).
Lasa, M., Brook, M., Saklatvala, J. & Clark, A. R. Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol. Cell. Biol. 21, 771–780 (2001).
Smoak, K. & Cidlowski, J. A. Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling. Mol. Cell. Biol. 26, 9126–9135 (2006).
Ishmael, F. T. et al. Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. J. Immunol. 180, 8342–8353 (2008).
Ishmael, F. T. et al. The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif. J. Immunol. 186, 1189–1198 (2011). This was the first demonstration of a direct and functional interaction between a nuclear receptor and mRNAs, the levels of which it regulates.
Dhawan, L., Liu, B., Blaxall, B. C. & Taubman, M. B. A novel role for the glucocorticoid receptor in the regulation of monocyte chemoattractant protein-1 mRNA stability. J. Biol. Chem. 282, 10146–10152 (2007).
Yang, F. & Schoenberg, D. R. Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA. Mol. Cell 14, 435–445 (2004).
Yang, F., Peng, Y. & Schoenberg, D. R. Endonuclease-mediated mRNA decay requires tyrosine phosphorylation of polysomal ribonuclease 1 (PMR1) for the targeting and degradation of polyribosome-bound substrate mRNA. J. Biol. Chem. 279, 48993–49002 (2004).
Peng, Y. & Schoenberg, D. R. c-Src activates endonuclease-mediated mRNA decay. Mol. Cell 25, 779–787 (2007).
Peng, Y., Murray, E. L., Sarkar, M., Liu, X. & Schoenberg, D. R. The cytoskeleton-associated Ena/VASP proteins are unanticipated partners of the PMR1 mRNA endonuclease. RNA 15, 576–587 (2009).
Tirasophon, W., Lee, K., Callaghan, B., Welihinda, A. & Kaufman, R. J. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev. 14, 2725–2736 (2000).
Han, D. et al. IRE1α kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562–575 (2009).
Hollien, J. et al. Regulated IRE1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323–331 (2009). The above two references described the endonuclease decay of endoplasmic-reticulumassociated mRNAs catalysed by IRE1 in response to endoplasmic reticulum stress during the unfolded protein response.
Anderson, P. & Kedersha, N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nature Rev. Mol. Cell. Biol. 10, 430–436 (2009).
Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185–1190 (2009).
Mizgalska, D. et al. Interleukin-1-inducible MCPIP protein has structural and functional properties of RNase and participates in degradation of IL-1β mRNA. FEBS J. 276, 7386–7399 (2009).
Paschoud, S. et al. Destabilization of interleukin-6 mRNA requires a putative RNA stem-loop structure, an AU-rich element, and the RNA-binding protein AUF1. Mol. Cell. Biol. 26, 8228–8241 (2006).
Suzuki, H. I. et al. MCPIP1 ribonuclease antagonizes Dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol. Cell 44, 424–436 (2011). This paper described a new mechanism whereby endonucleolytic cleavage in the unpaired loop of a pre-miRNA prior to its processing by Dicer regulates the abundance of mature miRNA. This has broad implications for the action of other endonucleases in regulating the biogenesis of regulatory RNAs.
Karginov, F. V. et al. Diverse endonucleolytic cleavage sits in the mammalian transcriptome depend on microRNAs, Drosha and additional nucleases. Mol. Cell 38, 781–788 (2010).
Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P. P. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).
Lykke-Andersen, S., Tomecki, R., Jensen, T. H. & Dziembowski, A. The eukaryotic RNA exosome: same scaffold but variable catalytic subunits. RNA Biol. 8, 61–66 (2011).
Kim, Y. K., Furic, L., Desgroseillers, L. & Maquat, L. E. Mammalian Staufen1 recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay. Cell 120, 195–208 (2005).
Hosoda, N., Kim, Y. K., Lejeune, F. & Maquat, L. E. CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells. Nature Struct. Mol. Biol. 12, 893–901 (2005).
Dominski, Z. & Marzluff, W. F. Formation of the 3′ end of histone mRNA: getting closer to the end. Gene 396, 373–390 (2007).
Tian, B., Hu, J., Zhang, H. & Lutz, C. S. A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res. 33, 201–212 (2005).
Yan, J. & Marr, T. G. Computational analysis of 3′-ends of ESTs shows four classes of alternative polyadenylation in human, mouse, and rat. Genome Res. 15, 369–375 (2005).
Flavell, S. W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008).
Laishram, R. S., Barlow, C. A. & Anderson, R. A. CKI isoforms α and ɛ regulate Star-PAP target messages by controlling Star–PAP poly(A) polymerase activity and phosphoinositide stimulation. Nucleic Acids Res. 39, 7961–7973 (2011).
Sandler, H. & Stoecklin, G. Control of mRNA decay by phosphorylation of tristetraprolin. Biochem. Soc. Trans. 36, 491–496 (2008).
Tarpey, P. S. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nature Genet. 39, 1127–1133 (2007).
Nguyen, L. S. et al. Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol. Psychiatry 20 Dec 2011 (doi:10.1038/mp.2011.163). This paper demonstrated the importance of UPF3X in regulating the neuronal cell transcriptome. Also, together with reference 27, this work correlated disease severity in UPF3X-deficient patients with the compensatory level of UPF3A.
Xin, H. et al. Association of the von Hippel–Lindau protein with AUF1 and post-transcriptional regulation of vascular endothelial growth factor A mRNA. Mol. Cancer Res. 15 Nov 2011 (doi:10.1158/1541-7786.mcr-11-0435).
Scheinman, R. I., Trivedi, R., Vermillion, S. & Kompella, U. B. Functionalized STAT1 siRNA nanoparticles regress rheumatoid arthritis in a mouse model. Nanomedicine 6, 1699–1682 (2011).
Yamashita, A. et al. SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes Dev. 23, 1091–1105 (2009).
Unterholzner, L. & Izaurralde, E. SMG7 acts as a molecular link between mRNA surveillance and mRNA decay. Mol. Cell 16, 587–596 (2004).
Huntzinger, E., Kashima, I., Fauser, M., Sauliere, J. & Izaurralde, E. SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA 14, 2609–2617 (2008).
Eberle, A. B., Lykke-Andersen, S., Muhlemann, O. & Jensen, T. H. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nature Struct. Mol. Biol. 16, 49–55 (2009).
Franks, T. M., Singh, G. & Lykke-Andersen, J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell 143, 938–950 (2010).
Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nature Rev. Mol. Cell. Biol. 10, 307–318 (2009).
Ma, X. M., Yoon, S. O., Richardson, C. J., Julich, K. & Blenis, J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133, 303–313 (2008).
Acknowledgements
We thank M. Gorospe for her helpful comments and C. Gong for assistance constructing figures. We also apologize to colleagues whose work we could not cite because of page and/or reference limitations. Research in the Schoenberg and Maquat laboratories is supported by grants from the US National Institute of General Medical Sciences.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Nonsense-mediated mRNA decay
-
(NMD). In mammalian cells, this pathway targets newly synthesized mRNAs undergoing a pioneer round of translation. It generally eliminates spliced mRNAs that prematurely terminate translation but also has some physiologic targets. It competes with STAU1-mediated mRNA decay.
- No-go mRNA decay
-
A pathway that degrades faulty mRNAs associated with stalled ribosomes. Decay is initiated by endonucleolytic cleavage near the stall site to release sequestered ribosomes and associated translation factors for the translation of other mRNAs.
- Non-stop mRNA decay
-
A pathway that degrades mRNAs lacking a stop codon and, thus, direct translation either through the poly(A) tail owing to, for example, premature polyadenylation, or to an mRNA breakpoint. It facilitates the recycling of ribosomes and translation factors.
- Exon junction complex
-
(EJC). A protein complex that is deposited ~20–24 nucleotides upstream of splicing-generated exon–exon junctions. It includes the nonsense-mediated mRNA decay factors UPF3X and UPF3 among many other factors.
- Premature termination codon
-
(PTC). A stop codon that is positioned 5′ to the normal termination codon. It usually activates nonsense-mediated mRNA decay when situated >50 nucleotides upstream of a splicing-generated exon–exon junction.
- SURF
-
A complex of SMG1, UPF1, eRF1 and eRF3 that recognizes a premature termination codon.
- Mammalian target rapamycin complex 1
-
(mTORC1). This complex consists of the phosphatidylinositol 3 kinase (PIK)-related serine/threonine protein kinase mTOR, raptor and LST8. mTORC1 is inhibited by low nutrient levels, growth factor deprivation and other stresses so that cellular protein synthesis is concomitantly inhibited.
- STAU1-mediated mRNA decay
-
(SMD). A pathway that degrades mRNAs that harbour a STAU1-binding site within their 3′ untranslated region. It depends on translation and on the nonsense-mediated mRNA factor UPF1.
- Alternative cleavage and polyadenylation
-
(APA). Provides a means to vary mRNA 3′ end formation and, thus, the regulatory sequences often present within 3′ untranslated region sequences.
- Mitogen-activated protein kinase
-
(MAPK). Proteins of this sort function in signal transduction by amplifying and integrating signals from different receptors followed by delivering each signal to one or more endpoint effector proteins.
- 14-3-3 adaptor proteins
-
A group of seven ubiquitously expressed phosphoserine/phosphothreonine-binding proteins. They can assemble into homo- or heterodimers, mediate protein–protein interactions and function in many cellular processes.
- Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation
-
(PAR-CLIP). A method for profiling RNA that is bound to a specific protein. Cells are grown in a medium containing 4-thiouridine or 6-thioguanosine, which, when it is incorporated into RNA, allows for efficient ultraviolet crosslinking to RNA-binding proteins. The immunoprecipitated protein–RNA complexes are then used to generate libraries for deep sequencing.
- RNA-binding protein immunoprecipitation
-
(RIP). A method for recovering RNAs by virtue of their binding by a particular protein. This uses either an antibody specific to a particular RNA-binding protein or antibody to an epitope tag on a recombinant protein expressed in target cells.
- Stress granules
-
Large cytoplasmic foci containing non-translating mRNAs bound by the 40S ribosomal subunit. They accumulate in stressed cells, commonly as a result of translation inhibition that is secondary to the phosphorylation of eIF2α.
- P bodies
-
Processing bodies, or P bodies, are small cytoplasmic RNA granules that are enriched for decapping proteins, activators of decapping, XRN1 and non-translating mRNAs. P bodies function as sites for mRNA storage and possibly decay.
- Toll-like receptors
-
Single-chain, membrane-bound receptors that function in the innate immune response. Binding of bacterial cell wall components, such as lipopolysaccharides or lipomannins, activates binding of adaptor proteins that leads to the activation of NFκB and associated changes in transcription.
Rights and permissions
About this article
Cite this article
Schoenberg, D., Maquat, L. Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13, 246–259 (2012). https://doi.org/10.1038/nrg3160
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg3160
This article is cited by
-
Molecular mechanism of specific HLA-A mRNA recognition by the RNA-binding-protein hMEX3B to promote tumor immune escape
Communications Biology (2024)
-
Single-molecule visualization of mRNA circularization during translation
Experimental & Molecular Medicine (2023)
-
An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus
Nature Cell Biology (2023)
-
Biomolecular condensates in kidney physiology and disease
Nature Reviews Nephrology (2023)
-
Ceg1 depletion reveals mechanisms governing degradation of non-capped RNAs in Saccharomyces cerevisiae
Communications Biology (2023)