New insights into decapping enzymes and selective mRNA decay

Advanced Review

Ewa Grudzien‐Nogalska, Megerditch Kiledjian

Published Online: Jul 17 2016

DOI: 10.1002/wrna.1379

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Removal of the 5′ end cap is a critical determinant controlling mRNA stability and efficient gene expression. Removal of the cap is exquisitely controlled by multiple direct and indirect regulators that influence association with the cap and the catalytic step. A subset of these factors directly stimulate activity of the decapping enzyme, while others influence remodeling of factors bound to mRNA and indirectly stimulate decapping. Furthermore, the components of the general decapping machinery can also be recruited by mRNA‐specific regulatory proteins to activate decapping. The Nudix hydrolase, Dcp2, identified as a first decapping enzyme, cleaves capped mRNA and initiates 5′–3′ degradation. Extensive studies on Dcp2 led to broad understanding of its activity and the regulation of transcript specific decapping and decay. Interestingly, seven additional Nudix proteins possess intrinsic decapping activity in vitro and at least two, Nudt16 and Nudt3, are decapping enzymes that regulate mRNA stability in cells. Furthermore, a new class of decapping proteins within the DXO family preferentially function on incompletely capped mRNAs. Importantly, it is now evident that each of the characterized decapping enzymes predominantly modulates only a subset of mRNAs, suggesting the existence of multiple decapping enzymes functioning in distinct cellular pathways. WIREs RNA 2017, 8:e1379. doi: 10.1002/wrna.1379 This article is categorized under: RNA Processing > Capping and 5′ End Modifications RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

Schematic representation of the Nudix proteins with decapping activity. Nudix proteins with decapping activity are aligned relative to their Nudix motif. The human Dcp2 protein is schematically depicted at the top with the evolutionarily conserved domains, with Nudix motif (red), Box A (green), Box B (blue) and regulatory domains encompassing the binding sites for Hedls (orange) and ubiquitin ligases (orange with stripes).

[ Normal View | Magnified View ]

A summary of the predominant cleavage site(s) within the cap triphosphate bridge for Nudix proteins with decapping activity. The position of the α, β and γ phosphates are shown with the cleave sites indicated by the arrow.

[ Normal View | Magnified View ]

Schematic representation of the yeast Dcp2p decapping protein and its interacting partners. Saccharomyces cerevisiae Dcp2p is schematically depicted with Nudix motif (red), Box A (green), Box B (blue), cis‐inhibitory element (gray) and binding sites for Dcp1p, Edc3p, Pat1p and Upf1p interacting proteins denoted along with their corresponding amino acid regions numbered.

[ Normal View | Magnified View ]

References

Muthukrishnan, S, Both, GW, Furuichi, Y, Shatkin, AJ. 5′‐Terminal 7‐methylguanosine in eukaryotic mRNA is required for translation. Nature 1975, 255:33–37.
Topisirovic, I, Svitkin, YV, Sonenberg, N, Shatkin, AJ. Cap and cap‐binding proteins in the control of gene expression. Wiley Interdiscip Rev RNA 2011, 2:277–298.
Konarska, MM, Padgett, RA, Sharp, PA. Recognition of cap structure in splicing in vitro of mRNA precursors. Cell 1984, 38:731–736.
Edery, I, Sonenberg, N. Cap‐dependent RNA splicing in a HeLa nuclear extract. Proc Natl Acad Sci U S A 1985, 82:7590–7594.
Visa, N, Izaurralde, E, Ferreira, J, Daneholt, B, Mattaj, IW. A nuclear cap‐binding complex binds Balbiani ring pre‐mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export. J Cell Biol 1996, 133:5–14.
Sonenberg, N, Rupprecht, KM, Hecht, SM, Shatkin, AJ. Eukaryotic mRNA cap binding protein: purification by affinity chromatography on sepharose‐coupled m7GDP. Proc Natl Acad Sci U S A 1979, 76:4345–4349.
Furuichi, Y, LaFiandra, A, Shatkin, AJ. 5′‐Terminal structure and mRNA stability. Nature 1977, 266:235–239.
Hsu, CL, Stevens, A. Yeast cells lacking 5′–%3E3′ exoribonuclease 1 contain mRNA species that are poly(A) deficient and partially lack the 5′ cap structure. Mol Cell Biol 1993, 13:4826–4835.
Sachs, AB. Messenger RNA degradation in eukaryotes. Cell 1993, 74:413–421.
Franks, TM, Lykke‐Andersen, J. The control of mRNA decapping and P‐body formation. Mol Cell 2008, 32:605–615.
Dunckley, T, Parker, R. The DCP2 protein is required for mRNA decapping in Saccharomyces cerevisiae and contains a functional MutT motif. EMBO J 1999, 18:5411–5422.
Lykke‐Andersen, J. Identification of a human decapping complex associated with hUpf proteins in nonsense‐mediated decay. Mol Cell Biol 2002, 22:8114–8121.
van Dijk, E, Cougot, N, Meyer, S, Babajko, S, Wahle, E, Seraphin, B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J 2002, 21:6915–6924.
Wang, Z, Jiao, X, Carr‐Schmid, A, Kiledjian, M. The hDcp2 protein is a mammalian mRNA decapping enzyme. Proc Natl Acad Sci U S A 2002, 99:12663–12668.
Song, MG, Li, Y, Kiledjian, M. Multiple mRNA decapping enzymes in mammalian cells. Mol Cell 2010, 40:423–432.
Jiao, X, Xiang, S, Oh, C, Martin, CE, Tong, L, Kiledjian, M. Identification of a quality‐control mechanism for mRNA 5′‐end capping. Nature 2010, 467:608–611.
Grudzien‐Nogalska, E, Jiao, X, Song, MG, Hart, RP, Kiledjian, M. Nudt3 is an mRNA decapping enzyme that modulates cell migration. RNA 2016, 22:773–781.
Bessman, MJ, Frick, DN, O`Handley, SF. The MutT proteins or "Nudix" hydrolases, a family of versatile, widely distributed, "housecleaning" enzymes. J Biol Chem 1996, 271:25059–25062.
Steiger, M, Carr‐Schmid, A, Schwartz, DC, Kiledjian, M, Parker, R. Analysis of recombinant yeast decapping enzyme. RNA 2003, 9:231–238.
Piccirillo, C, Khanna, R, Kiledjian, M. Functional characterization of the mammalian mRNA decapping enzyme hDcp2. RNA 2003, 9:1138–1147.
She, M, Decker, CJ, Svergun, DI, Round, A, Chen, N, Muhlrad, D, Parker, R, Song, H. Structural basis of dcp2 recognition and activation by dcp1. Mol Cell 2008, 29:337–349.
Li, Y, Kiledjian, M. Regulation of mRNA decapping. Wiley Interdiscip Rev RNA 2010, 1:253–265.
Ling, SH, Qamra, R, Song, H. Structural and functional insights into eukaryotic mRNA decapping. Wiley Interdiscip Rev RNA 2011, 2:193–208.
Arribas‐Layton, M, Wu, D, Lykke‐Andersen, J, Song, H. Structural and functional control of the eukaryotic mRNA decapping machinery. Biochim Biophys Acta 2013, 1829:580–589.
Parker, R. RNA degradation in Saccharomyces cerevisae. Genetics 2012, 191:671–702.
Floor, SN, Jones, BN, Hernandez, GA, Gross, JD. A split active site couples cap recognition by Dcp2 to activation. Nat Struct Mol Biol 2010, 17:1096–1101.
Borja, MS, Piotukh, K, Freund, C, Gross, JD. Dcp1 links coactivators of mRNA decapping to Dcp2 by proline recognition. RNA 2011, 17:278–290.
Valkov, E, Muthukumar, S, Chang, CT, Jonas, S, Weichenrieder, O, Izaurralde, E. Structure of the Dcp2‐Dcp1 mRNA‐decapping complex in the activated conformation. Nat Struct Mol Biol 2016, 23:574–579.
Fenger‐Gron, M, Fillman, C, Norrild, B, Lykke‐Andersen, J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Mol Cell 2005, 20:905–915.
Xu, J, Yang, JY, Niu, QW, Chua, NH. Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development. Plant Cell 2006, 18:3386–3398.
Hatfield, L, Beelman, CA, Stevens, A, Parker, R. Mutations in trans‐acting factors affecting mRNA decapping in Saccharomyces cerevisiae. Mol Cell Biol 1996, 16:5830–5838.
Nissan, T, Rajyaguru, P, She, M, Song, H, Parker, R. Decapping activators in Saccharomyces cerevisiae act by multiple mechanisms. Mol Cell 2010, 39:773–783.
Tharun, S, He, W, Mayes, AE, Lennertz, P, Beggs, JD, Parker, R. Yeast Sm‐like proteins function in mRNA decapping and decay. Nature 2000, 404:515–518.
Decker, CJ, Teixeira, D, Parker, R. Edc3p and a glutamine/asparagine‐rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J Cell Biol 2007, 179:437–449.
Fischer, N, Weis, K. The DEAD box protein Dhh1 stimulates the decapping enzyme Dcp1. EMBO J 2002, 21:2788–2797.
Coller, JM, Tucker, M, Sheth, U, Valencia‐Sanchez, MA, Parker, R. The DEAD box helicase, Dhh1p, functions in mRNA decapping and interacts with both the decapping and deadenylase complexes. RNA 2001, 7:1717–1727.
Haas, G, Braun, JE, Igreja, C, Tritschler, F, Nishihara, T, Izaurralde, E. HPat provides a link between deadenylation and decapping in metazoa. J Cell Biol 2010, 189:289–302.
Ozgur, S, Chekulaeva, M, Stoecklin, G. Human Pat1b connects deadenylation with mRNA decapping and controls the assembly of processing bodies. Mol Cell Biol 2010, 30:4308–4323.
Ahmed, I, Buchert, R, Zhou, M, Jiao, X, Mittal, K, Sheikh, TI, Scheller, U, Vasli, N, Rafiq, MA, Brohi, MQ, et al. Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Hum Mol Genet 2015, 24:3172–3180.
Eulalio, A, Rehwinkel, J, Stricker, M, Huntzinger, E, Yang, SF, Doerks, T, Dorner, S, Bork, P, Boutros, M, Izaurralde, E. Target‐specific requirements for enhancers of decapping in miRNA‐mediated gene silencing. Genes Dev 2007, 21:2558–2570.
Badis, G, Saveanu, C, Fromont‐Racine, M, Jacquier, A. Targeted mRNA degradation by deadenylation‐independent decapping. Mol Cell 2004, 15:5–15.
Tritschler, F, Eulalio, A, Truffault, V, Hartmann, MD, Helms, S, Schmidt, S, Coles, M, Izaurralde, E, Weichenrieder, O. A divergent Sm fold in EDC3 proteins mediates DCP1 binding and P‐body targeting. Mol Cell Biol 2007, 27:8600–8611.
Harigaya, Y, Jones, BN, Muhlrad, D, Gross, JD, Parker, R. Identification and analysis of the interaction between Edc3 and Dcp2 in Saccharomyces cerevisiae. Mol Cell Biol 2010, 30:1446–1456.
Chowdhury, A, Mukhopadhyay, J, Tharun, S. The decapping activator Lsm1p‐7p‐Pat1p complex has the intrinsic ability to distinguish between oligoadenylated and polyadenylated RNAs. RNA 2007, 13:998–1016.
Johansson, MJ, He, F, Spatrick, P, Li, C, Jacobson, A. Association of yeast Upf1p with direct substrates of the NMD pathway. Proc Natl Acad Sci U S A 2007, 104:20872–20877.
He, F, Li, C, Roy, B, Jacobson, A. Yeast Edc3 targets RPS28B mRNA for decapping by binding to a 3′ untranslated region decay‐inducing regulatory element. Mol Cell Biol 2014, 34:1438–1451.
He, F, Jacobson, A. Control of mRNA decapping by positive and negative regulatory elements in the Dcp2 C‐terminal domain. RNA 2015, 21:1633–1647.
Li, Y, Song, MG, Kiledjian, M. Transcript‐specific decapping and regulated stability by the human Dcp2 decapping protein. Mol Cell Biol 2008, 28:939–948.
Li, Y, Ho, ES, Gunderson, SI, Kiledjian, M. Mutational analysis of a Dcp2‐binding element reveals general enhancement of decapping by 5′‐end stem‐loop structures. Nucleic Acids Res 2009, 37:2227–2237.
Barreau, C, Paillard, L, Osborne, HB. AU‐rich elements and associated factors: are there unifying principles? Nucleic Acids Res 2005, 33:7138–7150.
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 2005, 19:351–361.
Murray, EL, Schoenberg, DR. A+U‐rich instability elements differentially activate 5′‐3′ and 3′‐5′ mRNA decay. Mol Cell Biol 2007, 27:2791–2799.
Parker, R, Song, H. The enzymes and control of eukaryotic mRNA turnover. Nat Struct Mol Biol 2004, 11:121–127.
Song, M, Kiledjian, M. 3′ Terminal oligo U‐tract‐mediated stimulation of decapping. RNA 2007, 13:2356–2365.
Mullen, TE, Marzluff, WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5′ to 3′ and 3′ to 5′. Genes Dev 2008, 22:50–65.
Hoefig, KP, Rath, N, Heinz, GA, Wolf, C, Dameris, J, Schepers, A, Kremmer, E, Ansel, KM, Heissmeyer, V. Eri1 degrades the stem‐loop of oligouridylated histone mRNAs to induce replication‐dependent decay. Nat Struct Mol Biol 2013, 20:73–81.
Slevin, MK, Meaux, S, Welch, JD, Bigler, R, Miliani de Marval, PL, Su, W, Rhoads, RE, Prins, JF, Marzluff, WF. Deep sequencing shows multiple oligouridylations are required for 3′ to 5′ degradation of histone mRNAs on polyribosomes. Mol Cell 2014, 53:1020–1030.
Shen, B, Goodman, HM. Uridine addition after microRNA‐directed cleavage. Science 2004, 306:997.
Chang, H, Lim, J, Ha, M, Kim, VN. TAIL‐seq: genome‐wide determination of poly(A) tail length and 3′ end modifications. Mol Cell 2014, 53:1044–1052.
Knusel, S, Roditi, I. Insights into the regulation of GPEET procyclin during differentiation from early to late procyclic forms of Trypanosoma brucei. Mol Biochem Parasitol 2013, 191:66–74.
Rissland, OS, Norbury, CJ. Decapping is preceded by 3′ uridylation in a novel pathway of bulk mRNA turnover. Nat Struct Mol Biol 2009, 16:616–623.
Sement, FM, Ferrier, E, Zuber, H, Merret, R, Alioua, M, Deragon, JM, Bousquet‐Antonelli, C, Lange, H, Gagliardi, D. Uridylation prevents 3′ trimming of oligoadenylated mRNAs. Nucleic Acids Res 2013, 41:7115–7127.
Thomas, MP, Liu, X, Whangbo, J, McCrossan, G, Sanborn, KB, Basar, E, Walch, M, Lieberman, J. Apoptosis triggers specific, rapid, and global mRNA decay with 3′ uridylated intermediates degraded by DIS3L2. Cell Rep 2015, 11:1079–1089.
Erickson, SL, Corpuz, EO, Maloy, JP, Fillman, C, Webb, K, Bennett, EJ, Lykke‐Andersen, J. Competition between decapping complex formation and ubiquitin‐mediated proteasomal degradation controls human Dcp2 decapping activity. Mol Cell Biol 2015, 35:2144–2153.
Nagaraj, N, Wisniewski, JR, Geiger, T, Cox, J, Kircher, M, Kelso, J, Paabo, S, Mann, M. Deep proteome and transcriptome mapping of a human cancer cell line. Mol Syst Biol 2011, 7:548.
Hu, G, McQuiston, T, Bernard, A, Park, YD, Qiu, J, Vural, A, Zhang, N, Waterman, SR, Blewett, NH, Myers, TG, et al. A conserved mechanism of TOR‐dependent RCK‐mediated mRNA degradation regulates autophagy. Nat Cell Biol 2015, 17:930–942.
Li, Y, Dai, J, Song, M, Fitzgerald‐Bocarsly, P, Kiledjian, M. Dcp2 decapping protein modulates mRNA stability of the critical interferon regulatory factor (IRF) IRF‐7. Mol Cell Biol 2012, 32:1164–1172.
Castellanos‐Rubio, A, Fernandez‐Jimenez, N, Kratchmarov, R, Luo, X, Bhagat, G, Green, PH, Schneider, R, Kiledjian, M, Bilbao, JR, Ghosh, S. A long noncoding RNA associated with susceptibility to celiac disease. Science 2016, 352:91–95.
Ghosh, T, Peterson, B, Tomasevic, N, Peculis, BA. Xenopus U8 snoRNA binding protein is a conserved nuclear decapping enzyme. Mol Cell 2004, 13:817–828.
Taylor, MJ, Peculis, BA. Evolutionary conservation supports ancient origin for Nudt16, a nuclear‐localized, RNA‐binding, RNA‐decapping enzyme. Nucleic Acids Res 2008, 36:6021–6034.
Lu, G, Zhang, J, Li, Y, Li, Z, Zhang, N, Xu, X, Wang, T, Guan, Z, Gao, GF, Yan, J. hNUDT16: a universal decapping enzyme for small nucleolar RNA and cytoplasmic mRNA. Protein Cell 2011, 2:64–73.
Li, Y, Song, M, Kiledjian, M. Differential utilization of decapping enzymes in mammalian mRNA decay pathways. RNA 2011, 17:419–428.
McLennan, AG. The Nudix hydrolase superfamily. Cell Mol Life Sci 2006, 63:123–143.
Song, MG, Bail, S, Kiledjian, M. Multiple Nudix family proteins possess mRNA decapping activity. RNA 2013, 19:390–399.
Otsuka, Y, Kedersha, NL, Schoenberg, DR. Identification of a cytoplasmic complex that adds a cap onto 5′‐monophosphate RNA. Mol Cell Biol 2009, 29:2155–2167.
Mukherjee, C, Patil, DP, Kennedy, BA, Bakthavachalu, B, Bundschuh, R, Schoenberg, DR. Identification of cytoplasmic capping targets reveals a role for cap homeostasis in translation and mRNA stability. Cell Rep 2012, 2:674–684.
Iyama, T, Abolhassani, N, Tsuchimoto, D, Nonaka, M, Nakabeppu, Y. NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single‐strand breaks in nuclear DNA and growth arrest. Nucleic Acids Res 2010, 38:4834–4843.
Abolhassani, N, Iyama, T, Tsuchimoto, D, Sakumi, K, Ohno, M, Behmanesh, M, Nakabeppu, Y. NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals. Nucleic Acids Res 2010, 38:2891–2903.
Wang, Z, Kiledjian, M. Functional link between the mammalian exosome and mRNA decapping. Cell 2001, 107:751–762.
Liu, H, Rodgers, ND, Jiao, X, Kiledjian, M. The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases. EMBO J 2002, 21:4699–4708.
Gu, M, Fabrega, C, Liu, SW, Liu, H, Kiledjian, M, Lima, CD. Insights into the structure, mechanism, and regulation of scavenger mRNA decapping activity. Mol Cell 2004, 14:67–80.
Taverniti, V, Seraphin, B. Elimination of cap structures generated by mRNA decay involves the new scavenger mRNA decapping enzyme Aph1/FHIT together with DcpS. Nucleic Acids Res 2015, 43:482–492.
Deana, A, Celesnik, H, Belasco, JG. The bacterial enzyme RppH triggers messenger RNA degradation by 5′ pyrophosphate removal. Nature 2008, 451:355–358.
Cahova, H, Winz, ML, Hofer, K, Nubel, G, Jaschke, A. NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs. Nature 2015, 519:374–377.
Jurado, AR, Tan, D, Jiao, X, Kiledjian, M, Tong, L. Structure and function of pre‐mRNA 5′‐end capping quality control and 3′‐end processing. Biochemistry 2014, 53:1882–1898.
Zhai, LT, Xiang, S. mRNA quality control at the 5′end. J Zhejiang Univ Sci B 2014, 15:438–443.
Xue, Y, Bai, X, Lee, I, Kallstrom, G, Ho, J, Brown, J, Stevens, A, Johnson, AW. Saccharomyces cerevisiae RAI1 (YGL246c) is homologous to human DOM3Z and encodes a protein that binds the nuclear exoribonuclease Rat1p. Mol Cell Biol 2000, 20:4006–4015.
Xiang, S, Cooper‐Morgan, A, Jiao, X, Kiledjian, M, Manley, JL, Tong, L. Structure and function of the 5′–%3E3′ exoribonuclease Rat1 and its activating partner Rai1. Nature 2009, 458:784–788.
Wang, VY, Jiao, X, Kiledjian, M, Tong, L. Structural and biochemical studies of the distinct activity profiles of Rai1 enzymes. Nucleic Acids Res 2015, 43:6596–6606.
Chang, JH, Jiao, X, Chiba, K, Oh, C, Martin, CE, Kiledjian, M, Tong, L. Dxo1 is a new type of eukaryotic enzyme with both decapping and 5′‐3′ exoribonuclease activity. Nat Struct Mol Biol 2012, 19:1011–1017.
Huh, WK, Falvo, JV, Gerke, LC, Carroll, AS, Howson, RW, Weissman, JS, O`Shea, EK. Global analysis of protein localization in budding yeast. Nature 2003, 425:686–691.
Jiao, X, Chang, JH, Kilic, T, Tong, L, Kiledjian, M. A mammalian pre‐mRNA 5′ end capping quality control mechanism and an unexpected link of capping to pre‐mRNA processing. Mol Cell 2013, 50:104–115.
Izaurralde, E, Lewis, J, McGuigan, C, Jankowska, M, Darzynkiewicz, E, Mattaj, IW. A nuclear cap binding protein complex involved in pre‐mRNA splicing. Cell 1994, 78:657–668.
Carlile, TM, Rojas‐Duran, MF, Zinshteyn, B, Shin, H, Bartoli, KM, Gilbert, WV. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 2014, 515:143–146.
Squires, JE, Patel, HR, Nousch, M, Sibbritt, T, Humphreys, DT, Parker, BJ, Suter, CM, Preiss, T. Widespread occurrence of 5‐methylcytosine in human coding and non‐coding RNA. Nucleic Acids Res 2012, 40:5023–5033.
Fu, L, Guerrero, CR, Zhong, N, Amato, NJ, Liu, Y, Liu, S, Cai, Q, Ji, D, Jin, SG, Niedernhofer, LJ, et al. Tet‐mediated formation of 5‐hydroxymethylcytosine in RNA. J Am Chem Soc 2014, 136:11582–11585.
Dominissini, D, Moshitch‐Moshkovitz, S, Schwartz, S, Salmon‐Divon, M, Ungar, L, Osenberg, S, Cesarkas, K, Jacob‐Hirsch, J, Amariglio, N, Kupiec, M, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A‐seq. Nature 2012, 485:201–206.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

New insights into decapping enzymes and selective mRNA decay

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox