Key Points
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RNA helicases of the DEAD box family are important players in RNA metabolism in most living organisms. Despite high conservation between DEAD box proteins, they participate in many different processes.
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Recent structural and functional analyses have changed our perception of these fascinating enzymes. They clamp the RNA substrate in an ATP-dependent manner, which can lead to the formation of an RNA-binding complex or to local unwinding of double-stranded RNA. Whereas ATP-binding is necessary and sufficient for RNA binding or unwinding, ATP hydrolysis is required for the release and recycling of the enzyme.
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The binding to the RNA substrate, or the unwinding of a duplex RNA and the hydrolysis of ATP and release of phosphate, must be tightly regulated by other proteins and small molecules. Therefore, DEAD box RNA helicases act in complexes that are sometimes very large.
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Three processes that beautifully exemplify these different concepts are the formation of the exon junction complex, the export of mRNA and translation initiation.
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In the exon junction complex, eukaryotic initiation factor 4AIII (eIF4AIII) is bound to the mRNA and the hydrolysis of ATP and release of phosphate are controlled by partner proteins.
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The export of mRNA through the nuclear complex involves many proteins. This process is assisted by DEAD box protein 5 (Dbp5) in yeast (DDX19 and DDX25 in vertebrates), which is required for the recycling of export factors and the release of the mRNA into the cytoplasm. Its activity is controlled by nuclear pore complex proteins and the small metabolite inositol hexakisphosphate.
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eIF4A, which was the first DEAD box protein to be characterized, is required for translation initiation. Its activity is stimulated by the interaction with eIF4G, which is a large scaffolding protein of the cap-binding complex, and inhibited by the tumour suppressor protein programmed cell death 4 (PDCD4), the small RNA BC1 or the small natural products pateamine A or hippuristanol.
Abstract
RNA helicases of the DEAD box family are present in all eukaryotic cells and in many bacteria and Archaea. These highly conserved enzymes are required for RNA metabolism from transcription to degradation and are therefore important players in gene expression. DEAD box proteins use ATP to unwind short duplex RNA in an unusual fashion and remodel RNA–protein complexes, but they can also function as ATP-dependent RNA clamps to provide nucleation centres that establish larger RNA–protein complexes. Structural, mechanistic and molecular biological studies have started to reveal how these conserved proteins can perform such diverse functions and how accessory proteins have a central role in their regulation.
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References
Jankowsky, E. RNA helicases at work: binding and rearranging. Trends Biochem. Sci. 36, 19–29 (2011).
Gorbalenya, A. E. & Koonin, E. V. Helicases: amino acid comparisons and structure–function relationships. Curr. Opin. Struct. Biol. 3, 419–429 (1993).
Fairman-Williams, M. E., Guenther, U. P. & Jankowsky, E. SF1 and SF2 helicases: family matters. Curr. Opin. Struct. Biol. 20, 313–324 (2010).
Singleton, M. R., Dillingham, M. S. & Wigley, D. B. Structure and mechanism of helicases and nucleic acid translocases. Ann. Rev. Biochem. 76, 23–50 (2007).
Cordin, O., Banroques, J., Tanner, N. K. & Linder, P. The DEAD-box protein family of RNA helicases. Gene 367, 17–37 (2006).
Jarmoskaite, I. & Russell, R. DEAD-box proteins as RNA helicases and chaperones. Wiley Interdiscip.Rev. RNA 2, 135–152 (2011).
Abdelhaleem, M. Do human RNA helicases have a role in cancer? Biochim. Biophys. Acta 1704, 37–46 (2004).
Caruthers, J. M. & McKay, D. B. Helicase structure and mechanism. Curr. Opin. Struct. Biol. 12, 123–133 (2002).
Linder, P. et al. Birth of the D-E-A-D box. Nature 337, 121–122 (1989).
Linder, P. Dead-box proteins: a family affair—active and passive players in RNP-remodeling. Nucleic Acids Res. 34, 4168–4180 (2006).
Hilbert, M., Karow, A. R. & Klostermeier, D. The mechanism of ATP-dependent RNA unwinding by DEAD-box proteins. Biol. Chem. 390, 1237–1250 (2009).
Strohmeier, J., Hertel, I., Diederichsen, U., Rudolph, M. G. & Klostermeier, D. Changing nucleotide specificity of the DEAD-box helicase Hera abrogates communication between the Q-motif and the P-loop. Biol. Chem. 392, 357–369 (2011).
Del Campo, M. & Lambowitz, A. M. Structure of the yeast DEAD box protein Mss116p reveals two wedges that crimp RNA. Mol. Cell 35, 598–609 (2009).
Sengoku, T., Nureki, O., Nakamura, A., Kobayashi, S. & Yokoyama, S. Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa. Cell 125, 287–300 (2006). The structure of Vasa in the presence of RNA showed for the first time a kinking of the substrate, which is indicative of a local unwinding mechanism.
Andersen, C. B. et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science 313, 1968–1972 (2006).
Bono, F., Ebert, J., Lorentzen, E. & Conti, E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006).
von Moeller, H., Basquin, C. & Conti, E. The mRNA export protein DBP5 binds RNA and the cytoplasmic nucleoporin NUP214 in a mutually exclusive manner. Nature Struct. Biol. 16, 247–254 (2009).
Fan, J. S. et al. Solution and crystal structures of mRNA exporter Dbp5p and its interaction with nucleotides. J. Mol. Biol. 388, 1–10 (2009).
Milner-White, E. J., Peitras, Z. & Luisi, B. F. An ancient anion-binding structural module in RNA and DNA helicases. Proteins 78, 1900–1908 (2010).
Banroques, J., Doère, M., Dreyfus, M., Linder, P. & Tanner, N. K. Motif III in superfamily 2 “helicases” helps convert the binding energy of ATP into a high-affinity RNA binding site in the yeast DEAD-box protein Ded1. J. Mol. Biol. 396, 949–966 (2010).
Hardin, J. W., Hu, Y. X. & McKay, D. B. Structure of the RNA binding domain of a DEAD-box helicase bound to its ribosomal RNA target reveals a novel mode of recognition by an RNA recognition motif. J. Mol. Biol. 402, 412–427 (2010).
Klostermeier, D. & Rudolph, M. G. A novel dimerization motif in the C-terminal domain of the Thermus thermophilus DEAD box helicase Hera confers substantial flexibility. Nucleic Acids Res. 37, 421–430 (2009).
Rudolph, M. G. & Klostermeier, D. The Thermus thermophilus DEAD box helicase Hera contains a modified RNA recognition motif domain loosely connected to the helicase core. RNA 15, 1993–2001 (2009).
Karow, A. R. & Klostermeier, D. A structural model for the DEAD box helicase YxiN in solution: localization of the RNA binding domain. J. Mol. Biol. 402, 629–637 (2010).
Tanner, N. K. & Linder, P. DExD/H box RNA helicases. From generic motors to specific dissociation functions. Mol. Cell 8, 251–261 (2001).
Jankowsky, E. & Fairman, M. RNA helicases — one fold for many functions. Curr. Opin. Struct. Biol. 17, 316–324 (2007).
Kuhn, B., Abdel-Monem, M., Krell, H. & Hoffman-Berling, H. Evidence for two mechanisms for DNA unwinding catalyzed by DNA helicases. J. Biol. Chem. 254, 11343–11350 (1979).
Rogers, G. W., Richter, N. J. & Merrick, W. C. Biochemical and kinetic characterization of the RNA helicase activity of eukaryotic initiation factor 4A. J. Biol. Chem. 274, 12236–12244 (1999).
Rogers, G. W. Jr, Lima, W. F. & Merrick, W. C. Further characterization of the helicase activity of eIF4A. Substrate specificity. J. Biol. Chem. 276, 12598–12608 (2001).
Yang, Q. & Jankowsky, E. The DEAD-box protein Ded1 unwinds RNA duplexes by a mode distinct from translocating helicases. Nature Struct. Mol. Biol. 13, 981–986 (2006).
Bizebard, T., Ferlenghi, I., Iost, I. & Dreyfus, M. Studies on three E. coli DEAD-box helicases point to an unwinding mechanism different from that of model DNA helicases. Biochemistry 43, 7857–7866 (2004).
Pyle, A. M. Translocation and unwinding mechanisms of RNA and DNA helicases. Ann. Rev. Biophys. 37, 317–336 (2008).
Tijerina, P., Bhaskaran, H. & Russell, R. Nonspecific binding to structured RNA and preferential unwinding of an exposed helix by the CYT-19 protein, a DEAD-box RNA chaperone. Proc. Natl Acad. Sci. USA 103, 16698–16703 (2006).
Yang, Q., Del Campo, M., Lambowitz, A. M. & Jankowsky, E. DEAD-box proteins unwind duplexes by local strand separation. Mol. Cell 28, 253–263 (2007).
Chen, J. Y.-F. et al. Specific alterations of U1-C protein or U1 small nuclear RNA can eliminate the requirement of Prp28p, an essential DEAD box splicing factor. Mol. Cell 7, 227–232 (2001). In vivo indication of RNPase activity by a DEAD box protein.
Staley, J. P. & Guthrie, C. An RNA switch at the 5′ splice site requires ATP and the DEAD box protein Prp28p. Mol. Cell 3, 55–64 (1999).
Madej, M. J., Niemann, M., Huttenhofer, A. & Goringer, H. U. Identification of novel guide RNAs from the mitochondria of Trypanosoma brucei. RNA Biol. 5, 84–91 (2008).
Tollervey, D. & Kiss, T. Function and synthesis of small nucleolar RNAs. Curr. Op. Cell Biol. 9, 337–342 (1997).
Chen, Y. et al. The DEAD-box protein CYT-19 uses a single ATP to completely separate a short RNA duplex. Proc. Natl Acad. Sci. USA 105, 20203–20208 (2008).
Henn, A. et al. Pathway of ATP utilization and duplex rRNA unwinding by the DEAD-box helicase, DbpA. Proc. Natl Acad. Sci. USA 107, 4046–4050 (2010).
Aregger, R. & Klostermeier, D. The DEAD box helicase YxiN maintains a closed conformation during ATP hydrolysis. Biochemistry 48, 10679–10681 (2009).
Liu, F., Putnam, A. & Jankowsky, E. ATP hydrolysis is required for DEAD-box protein recycling but not for duplex unwinding. Proc. Natl Acad. Sci. USA 105, 20209–20214 (2008).
Henn, A., Cao, W., Hackney, D. D. & De La Cruz, E. M. The ATPase cycle mechanism of the DEAD-box rRNA helicase, DbpA. J. Mol. Biol. 377, 193–205 (2008).
Nielsen, K. H. et al. Mechanism of ATP turnover inhibition in the EJC. RNA 15, 67–75 (2008).
Del Campo, M. et al. Unwinding by local strand separation is critical for the function of DEAD-box proteins as RNA chaperones. J. Mol. Biol. 389, 674–693 (2009).
Iost, I., Dreyfus, M. & Linder, P. Ded1p, a DEAD-box protein required for translation initiation in Saccharomyces cerevisiae, is an RNA helicase. J. Biol. Chem. 274, 17677–17683 (1999).
Kistler, A. L. & Guthrie, C. Deletion of MUD2, the yeast homolog of U2AF65, can bypass the requirement for Sub2, an essential spliceosomal ATPase. Genes Dev. 15, 42–49 (2001). In vivo indication of RNPase activity by a DEAD box protein.
Lund, M. K. & Guthrie, C. The DEAD-box protein Dbp5p is required to dissociate Mex67p from exported mRNPs at the nuclear rim. Mol. Cell 20, 645–651 (2005).
Fairman, M. et al. Protein displacement by DExH/D RNA helicases without duplex unwinding. Science 304, 730–734 (2004). References 48 and 49 reported the removal of proteins from RNA by DEAD box proteins and opened the vision of the broad activity range that these proteins can have.
Bowers, H. A. et al. Discriminatory RNP remodeling by the DEAD-box protein DED1. RNA 12, 903–912 (2006).
Tran, E. J., Zhou, Y., Corbett, A. H. & Wente, S. R. The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA:protein remodeling events. Mol. Cell 28, 850–859 (2007).
Jankowsky, E. & Bowers, H. Remodeling of ribonucleoprotein complexes with DExH/D RNA helicases. Nucleic Acids Res. 34, 4181–4188 (2006).
Jankowsky, E., Gross, C. H., Shuman, S. & Pyle, A. M. Active disruption of an RNA–protein interaction by a DExH/D RNA helicase. Science 291, 121–125 (2001).
Rossler, O. G., Straka, A. & Stahl, H. Rearrangement of structured RNA via branch migration structures catalysed by the highly related DEAD-box proteins p68 and p72. Nucleic Acids Res. 29, 2088–2096 (2001).
Chamot, D., Colvin, K. R., Kujat-Choy, S. L. & Owttrim, G. W. RNA structural rearrangement via unwinding and annealing by the cyanobacterial RNA helicase, CrhR. J. Biol. Chem. 280, 2036–2044 (2005).
Yang, Q. & Jankowsky, E. ATP- and ADP-dependent modulation of RNA unwinding and strand annealing activities by the DEAD-box protein DED1. Biochemistry 44, 13591–13601 (2005).
Halls, C. et al. Involvement of DEAD-box proteins in group I and group II intron splicing. biochemical characterization of Mss116p, ATP hydrolysis-dependent and -independent mechanisms, and general RNA chaperone activity. J. Mol. Biol. 365, 835–855 (2007).
Uhlmann-Schiffler, H., Jalal, C. & Stahl, H. Ddx42p—a human DEAD box protein with RNA chaperone activities. Nucleic Acids Res. 34, 10–22 (2006).
Valdez, B. C. Structural domains involved in the RNA folding activity of RNA helicase II/Gu protein. Eur. J. Biochem. 267, 6395–6402 (2000).
Yang, Q., Fairman, M. E. & Jankowsky, E. DEAD-box-protein-assisted RNA structure conversion towards and against thermodynamic equilibrium values. J. Mol. Biol. 368, 1087–1100 (2007).
Bhaskaran, H. & Russell, R. Kinetic redistribution of native and misfolded RNAs by a DEAD-box chaperone. Nature 449, 1014–1018 (2007).
Ballut, L. et al. The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity. Nature Struct. Mol. Biol. 12, 861–869 (2005). Biochemical studies on eIF4AIII and EJC components demonstrated the importance of the clamping function of eIF4AIII.
Le Hir, H., Izaurralde, E., Maquat, L. E. & Moore, M. J. The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon–exon junctions. EMBO J. 19, 6860–6869 (2000).
Le Hir, H. & Andersen, G. R. Structural insights into the exon junction complex. Curr. Opin. Struct. Biol. 18, 112–119 (2008).
Le Hir, H. & Séraphin, B. EJCs at the heart of translational control. Cell 133, 213–216 (2008).
Shibuya, T., Tange, T. O., Sonenberg, N. & Moore, M. J. eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nature Struct. Mol. Biol. 11, 346–351 (2004).
Palacios, I. M., Gatfield, D., St. Johnston, D. & Izaurralde, E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757 (2004).
Ferraiuolo, M. A. et al. A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in nonsense-mediated decay. Proc. Natl Acad. Sci. USA 101, 4118–4123 (2004). References 66–68 described the eIF4AIII-containing EJC as an RNA-bound quality control label.
Sauliere, J. et al. The exon junction complex differentially marks spliced junctions. Nature Struct. Mol. Biol. 17, 1269–1271 (2010).
Gehring, N. H., Lamprinaki, S., Kulozik, A. E. & Hentze, M. W. Disassembly of exon junction complexes by PYM. Cell 137, 536–548 (2009).
Noble, C. G. & Song, H. MLN51 stimulates the RNA-helicase activity of eIF4AIII. PLoS ONE 2, e303 (2007).
Shibuya, T., Tange, T. O., Stroupe, M. E. & Moore, M. J. Mutational analysis of human eIF4AIII identifies regions necessary for exon junction complex formation and nonsense-mediated mRNA decay. RNA 12, 360–374 (2006).
Nashchekin, D., Zhao, J., Visa, N. & Daneholt, B. A novel Ded1-like RNA helicase interacts with the Y-box protein ctYB-1 in nuclear mRNP particles and in polysomes. J. Biol. Chem. 281, 14263–14272 (2006).
Estruch, F. & Cole, C. N. An early function during transcription for the yeast mRNA export factor Dbp5p/Rat8p suggested by its genetic and physical interactions with transcription factor IIH components. Mol. Biol. Cell 14, 1664–1676 (2003).
Zhao, J., Jin, S. B., Bjorkroth, B., Wieslander, L. & Daneholt, B. The mRNA export factor Dbp5 is associated with Balbiani ring mRNP from gene to cytoplasm. EMBO J. 21, 1177–1187 (2002).
Parsyan, A. et al. mRNA helicases: the tacticians of translational control. Nature Rev. Mol. Cell Biol. 12, 235–245 (2011).
Rogers, G. W., Komar, A. A. & Merrick, W. C. eIF4A: The godfather of the DEAD-box helicases. Progr. Nucl. Acids Res. 72, 307–331 (2002).
Li, Q. et al. Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII. Mol. Cell. Biol. 19, 7336–7346 (1999).
Linder, P. Yeast RNA helicases of the DEAD-box family involved in translation initiation. Biol. Cell 95, 157–167 (2003).
Ray, B. K. et al. ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors. J. Biol. Chem. 260, 7651–7658 (1985).
von der Haar, T. & McCarthy, J. E. Intracellular translation initiation factor levels in Saccharomyces cerevisiae and their role in cap-complex function. Mol. Microbiol. 46, 531–544 (2002).
Duncan, R. & Hershey, J. W. B. Identification and quantification of levels of protein synthesis initiation factors in crude HeLa cell lysates by two-dimentional polyacrylamide gel electrophoresis. J. Biol. Chem. 258, 7228–7235 (1983).
Gingras, A. C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999).
Rozovsky, N., Butterworth, A. C. & Moore, M. J. Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. RNA 14, 2136–2148 (2008).
Rogers, G. W. Jr, Richter, N. J., Lima, W. F. & Merrick, W. C. Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. J. Biol. Chem. 276, 30914–30922 (2001).
Richter-Cook, N. J., Dever, T. E., Hensold, J. O. & Merrick, W. C. Purification and characterization of a new eukaryotic protein. J. Biol. Chem. 273, 7579–7587 (1998).
Rozen, F. et al. Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol. Cell. Biol. 10, 1134–1144 (1990). Demonstrated for the first time strand separation activity by a DEAD box protein.
Marintchev, A. et al. Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation. Cell 136, 447–460 (2009).
Schütz, P. et al. Crystal structure of the yeast eIF4A–eIF4G complex: an RNA-helicase controlled by protein–protein interactions. Proc. Natl Acad. Sci. USA 105, 9564–9569 (2006).
Oberer, M., Marintchev, A. & Wagner, G. Structural basis for the enhancement of eIF4A helicase activity by eIF4G. Genes Dev. 19, 2212–2223 (2005). A structural explanation of the previously observed stimulation of the eIF4A DEAD box protein by another protein.
Hilbert, M., Kebbel, F., Gubaev, A. & Klostermeier, D. eIF4G stimulates the activity of the DEAD box protein eIF4A by a conformational guidance mechanism. Nucleic Acids Res. 39, 2260–2270 (2011).
Nielsen, K. H. et al. Synergistic activation of eIF4A by eIF4B and eIF4G. Nucleic Acids Res. 39, 2678–2689 (2011).
Sonenberg, N. Cap-binding proteins of eukaryotic messenger RNA: functions in initiation and control of translation. Prog. Nucleic Acid Res. Mol. Biol. 35, 173–207 (1988).
Svitkin, Y. V. et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5′ secondary structure. RNA 7, 382–394 (2001).
Pestova, T. V. & Kolupaeva, V. G. The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. Genes Dev. 16, 2906–2922 (2002).
Berthelot, K., Muldoon, M., Rajkowitsch, L., Hughes, J. & McCarthy, J. E. Dynamics and processivity of 40S ribosome scanning on mRNA in yeast. Mol. Microbiol. 51, 987–1001 (2004).
Pisareva, V. P., Pisarev, A. V., Komar, A. A., Hellen, C. U. & Pestova, T. V. Translation initiation on mammalian mRNAs with structured 5′UTRs requires DExH-box protein DHX29. Cell 135, 1237–1250 (2008).
Sonenberg, N. & Dever, T. E. Eukaryotic translation initiation factors and regulators. Curr. Opin. Struct. Biol. 13, 56–63 (2003).
Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nature Rev. Mol. Cell Biol. 5, 827–835 (2004).
Sonenberg, N. eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. Biochem. Cell Biol. 86, 178–183 (2008).
Polunovsky, V. A. & Bitterman, P. B. The cap-dependent translation apparatus integrates and amplifies cancer pathways. RNA Biol. 3, 10–17 (2006).
Yang, H. S. et al. The transfromation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol. Cell. Biol. 23, 26–37 (2003).
Loh, P. G. et al. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J. 28, 274–285 (2009).
Suzuki, C. et al. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc. Natl Acad. Sci. USA 105, 3274–3279 (2008).
Lindqvist, L. et al. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE 3, e1583 (2008).
Bordeleau, M. E. et al. RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation. Chem. Biol. 13, 1287–1295 (2006).
Low, W. K. et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell 20, 709–722 (2005).
Dang, Y. et al. Inhibition of nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII. J. Biol. Chem. 284, 23613–23621 (2009).
Lin, D., Pestova, T. V., Hellen, C. U. & Tiedge, H. Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol. Cell. Biol. 28, 3008–3019 (2008).
Snay-Hodge, C. A., Colot, H. V., Goldstein, A. L. & Cole, C. N. Dbp5p/Rat8p is a yeast nuclear pore-associated DEAD-box protein essential for RNA export. EMBO J. 17, 2663–2676 (1998).
Tseng, S. S. et al. Dbp5p, a cytosolic RNA helicase, is required for poly(A)+ RNA export. EMBO J. 17, 2651–2662 (1998). References 110 and 111 provided the first descriptions of the involvement of Dbp5 in mRNA export.
Bolger, T. A., Folkmann, A. W., Tran, E. J. & Wente, S. R. The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 134, 624–633 (2008).
Gross, T. et al. The DEAD-box RNA helicase Dbp5 functions in translation termination. Science 315, 646–649 (2007).
Weirich, C. S. et al. Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export. Nature Cell Biol. 8, 668–676 (2006).
Alcazar-Roman, A. R., Tran, E. J., Guo, S. & Wente, S. R. Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nature Cell Biol. 8, 711–716 (2006).
Schmitt, C. et al. Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p. EMBO J. 18, 4332–4347 (1999).
Hodge, C. A., Colot, H. V., Stafford, P. & Cole, C. N. Rat8p/Dbp5p is a shuttling transport factor that interacts with Rat7p/Nup159p and Gle1p and suppresses the mRNA export defect of xpo1-1 cells. EMBO J. 18, 5778–5788 (1999).
Weirich, C. S., Erzberger, J. P., Berger, J. M. & Weis, K. The N-terminal domain of Nup159 forms a β-propeller that functions in mRNA export by tethering the helicase Dbp5 to the nuclear pore. Mol. Cell 16, 749–760 (2004).
Collins, R. et al. The DEXD/H-box RNA helicase DDX19 is regulated by an α-helical switch. J. Biol. Chem. 284, 10296–10300 (2009).
Strahm, Y. et al. The RNA export factor Gle1p is located on the cytoplasmic fibrils of the NPC and physically interacts with the FG-nucleoporin Rip1p, the DEAD-box protein Rat8p/Dbp5p and a new protein Ymr255p. EMBO J. 18, 5761–5777 (1999).
Montpetit, B. et al. A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature 472, 238–242 (2011). Extensive analysis of Dbp5 structure–function revealed similarities with the eIF4A–eIF4G interaction.
Ives, E. B., Nichols, J., Wente, S. R. & York, J. D. Biochemical and functional characterization of inositol 1,3,4,5,6-pentakisphosphate 2-kinases. J. Biol. Chem. 275, 36575–36583 (2000).
Noble, K. N. et al. The Dbp5 cycle at the nuclear pore complex during mRNA export II: nucleotide cycling and mRNP remodeling by Dbp5 are controlled by Nup159 and Gle1. Genes Dev. 25, 1065–1077 (2011).
Hodge, C. A. et al. The Dbp5 cycle at the nuclear pore complex during mRNA export I: dbp5 mutants with defects in RNA binding and ATP hydrolysis define key steps for Nup159 and Gle1. Genes Dev. 25, 1052–1064 (2011).
Tritschler, F. et al. Structural basis for the mutually exclusive anchoring of P body components EDC3 and Tral to the DEAD box protein DDX6/Me31B. Mol. Cell 33, 661–668 (2009).
Buchwald, G. et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc. Natl Acad. Sci. USA 107, 10050–10055 (2010).
Mohr, S., Stryker, J. M. & Lambowitz, A. M. A DEAD-box protein functions as an ATP-dependent RNA chaperone in group I intron splicing. Cell 109, 769–779 (2002).
Mohr, S., Matsuura, M., Perlman, P. S. & Lambowitz, A. M. A DEAD-box protein alone promotes group II intron splicing and reverse splicing by acting as an RNA chaperone. Proc. Natl Acad. Sci. USA 103, 3569–3574 (2006).
Fedorova, O., Solem, A. & Pyle, A. M. Protein-facilitated folding of group II intron ribozymes. J. Mol. Biol. 397, 799–813 (2010).
Karunatilaka, K. S., Solem, A., Pyle, A. M. & Rueda, D. Single-molecule analysis of Mss116-mediated group II intron folding. Nature 467, 935–939 (2010).
Shen, H. et al. Distinct activities of the DExD/H-box splicing factor hUAP56 facilitate stepwise assembly of the spliceosome. Genes Dev. 22, 1796–1803 (2008).
Kos, M. & Tollervey, D. The putative RNA helicase Dbp4p is required for release of the U14 snoRNA from preribosomes in Saccharomyces cerevisiae. Mol. Cell 20, 53–64 (2005).
Fuller-Pace, F. V. DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res. 34, 4206–4215 (2006).
Klappacher, G. W. et al. An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation. Cell 109, 169–180 (2002).
Watanabe, M. et al. A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor α coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. EMBO J. 20, 1341–1352 (2001).
Endoh, H. et al. Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α. Mol. Cell. Biol. 19, 5363–5372 (1999).
Bates, G. J. et al. The DEAD box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor. EMBO J. 24, 543–553 (2005).
Diges, C. M. & Uhlenbeck, O. C. Escherichia coli DbpA is an RNA helicase that requires hairpin 92 of 23S rRNA. EMBO J. 20, 5503–5512 (2001).
Bohnsack, M. T. et al. Prp43 bound at different sites on the pre-rRNA performs distinct functions in ribosome synthesis. Mol. Cell 36, 583–592 (2009).
Sekiguchi, T., Kurihara, Y. & Fukumura, J. Phosphorylation of threonine 204 of DEAD-box RNA helicase DDX3 by cyclin B/cdc2 in vitro. Biochem. Biophys. Res. Commun. 356, 668–673 (2007).
Jankowsky, E. & Fairman-Williams, M. E. In: RNA Helicases Vol. 19 Ch. 1 (ed. Jankowsky, E.) 1–31 (Royal Society of Chemistry, Cambridge, 2010).
Caruthers, J. M., Johnson, E. R. & McKay, D. B. Crystal structure of yeast initiation factor 4A, a DEAD-box RNA helicase. Proc. Natl Acad. Sci. USA 97, 13080–13085 (2000).
Acknowledgements
Work in the authors's laboratories is supported by the Swiss National Science Foundation and the Canton of Geneva (P.L.) and by the US National Institutes of Health (RO1GM006770) and the Burroughs Wellcome Fund (E.J.). The authors acknowledge the comments by the referees and the many generous and stimulating interactions in the DEAD box RNA helicase field. The authors apologize to all colleagues whose important contributions could not be highlighted or discussed here.
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DATABASES
FURTHER INFORMATION
Glossary
- Spliceosome
-
A large, dynamic complex that is composed of RNA and proteins and is involved in excising introns and joining the exons of pre-mRNA.
- Small nuclear RNA
-
(snRNA). RNA molecules that serve as guides during pre-mRNA processing.
- Small nucleolar RNA
-
(snoRNA). RNA molecules that serve as guides during pre-ribosomal RNA modification.
- Mitochondrial RNA editing
-
Guide RNA-assisted insertion and modification of the sequence of mitochondrial mRNA in trypanosomes.
- Transition state analogue
-
A compound that mimics the structure of the transition state, which is the state with the highest energy along the reaction coordinate.
- ATP ground state
-
In helicases, this typically corresponds to the reaction state when ATP is bound by the enzyme but is not yet hydrolysed.
- Nonsense-mediated RNA decay
-
(NMD). A process by which mRNA molecules that contain a stop codon within the open reading frame are subjected to rapid degradation to avoid synthesis of deleterious truncated proteins.
- Nuclear speckles
-
Subnuclear structures that are enriched with pre-mRNA and many different proteins that are involved in splicing.
- Next-generation sequencing
-
High-throughput sequencing technologies in which millions of (usually short) pieces of sequence are produced in parallel.
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Linder, P., Jankowsky, E. From unwinding to clamping — the DEAD box RNA helicase family. Nat Rev Mol Cell Biol 12, 505–516 (2011). https://doi.org/10.1038/nrm3154
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DOI: https://doi.org/10.1038/nrm3154
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