Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The multiple functions of RNA helicases as drivers and regulators of gene expression

Key Points

  • RNA helicases constitute a large family of proteins with functions in all aspects of RNA metabolism.

  • RNA helicases can have a variety of biochemical effects, such as unwinding or annealing RNA molecules, clamping protein complexes on RNA or remodelling ribonucleoprotein complexes.

  • Transcriptome analyses revealed selective effects of RNA helicases that can be controlled by cofactors, which often modulate their ATPase activity.

  • Most RNA helicases are involved in several steps of the gene expression process. Thus, they are important for coupling, coordinating and orchestrating gene expression steps and programmes.

  • RNA helicases function as drivers of some mRNAs from one processing factory to another, ending as part of a translationally active mRNA pool. They also can function as molecular switchers by orientating other mRNAs into unproductive pools, leading either to (transient) storage or to decay.

Abstract

RNA helicases comprise the largest family of enzymes involved in the metabolism of mRNAs, the processing and fate of which rely on their packaging into messenger ribonucleoprotein particles (mRNPs). In this Review, we describe how the capacity of some RNA helicases to either remodel or lock the composition of mRNP complexes underlies their pleiotropic functions at different steps of the gene expression process. We illustrate the roles of RNA helicases in coordinating gene expression steps and programmes, and propose that RNA helicases function as molecular drivers and guides of the progression of their mRNA substrates from one RNA-processing factory to another, to a productive mRNA pool that leads to protein synthesis or to unproductive mRNA pools that are stored or degraded.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanisms of action of RNA helicases.
Figure 2: The maturation and fate of an mRNA.
Figure 3: The multiple functions of RNA helicases.
Figure 4: Coupling, coordination and orchestration of gene expression processes by RNA helicases.
Figure 5: Model of the role of RNA helicases as drivers and switchers of the flow of genetic information.

Similar content being viewed by others

References

  1. Singh, G., Pratt, G., Yeo, G. W. & Moore, M. J. The clothes make the mRNA: past and present trends in mRNP fashion. Annu. Rev. Biochem. 84, 325–354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Mitchell, S. F. & Parker, R. Principles and properties of eukaryotic mRNPs. Mol. Cell 54, 547–558 (2014).

    CAS  PubMed  Google Scholar 

  3. Muller-McNicoll, M. & Neugebauer, K. M. How cells get the message: dynamic assembly and function of mRNA–protein complexes. Nat. Rev. Genet. 14, 275–287 (2013).

    PubMed  Google Scholar 

  4. Putnam, A. A. & Jankowsky, E. DEAD-box helicases as integrators of RNA, nucleotide and protein binding. Biochim. Biophys. Acta 1829, 884–893 (2013). This review describes all the biochemical activities of RNA helicases.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jankowsky, E. RNA helicases at work: binding and rearranging. Trends Biochem. Sci. 36, 19–29 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ozgur, S. et al. The conformational plasticity of eukaryotic RNA-dependent ATPases. FEBS J. 282, 850–863 (2015).

    CAS  PubMed  Google Scholar 

  7. Leitao, A. L., Costa, M. C. & Enguita, F. J. Unzippers, resolvers and sensors: a structural and functional biochemistry tale of RNA helicases. Int. J. Mol. Sci. 16, 2269–2293 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Jarmoskaite, I. & Russell, R. RNA helicase proteins as chaperones and remodelers. Annu. Rev. Biochem. 83, 697–725 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Linder, P. & Jankowsky, E. From unwinding to clamping — the DEAD box RNA helicase family. Nat. Rev. Mol. Cell Biol. 12, 505–516 (2011).

    CAS  PubMed  Google Scholar 

  10. Wu, Y. Unwinding and rewinding: double faces of helicase? J. Nucleic Acids 2012, 140601 (2012).

    PubMed  PubMed Central  Google Scholar 

  11. Martin, R., Straub, A. U., Doebele, C. & Bohnsack, M. T. DExD/H-box RNA helicases in ribosome biogenesis. RNA Biol. 10, 4–18 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fuller-Pace, F. V. DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res. 34, 4206–4215 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bentley, D. L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15, 163–175 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fu, X. D. & Ares, M. Jr. Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15, 689–701 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Witten, J. T. & Ule, J. Understanding splicing regulation through RNA splicing maps. Trends Genet. 27, 89–97 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Irimia, M. & Blencowe, B. J. Alternative splicing: decoding an expansive regulatory layer. Curr. Opin. Cell Biol. 24, 323–332 (2012).

    CAS  PubMed  Google Scholar 

  17. Guil, S. et al. Roles of hnRNP A1, SR proteins, and p68 helicase in c-H-ras alternative splicing regulation. Mol. Cell. Biol. 23, 2927–2941 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Honig, A., Auboeuf, D., Parker, M. M., O'Malley, B. W. & Berget, S. M. Regulation of alternative splicing by the ATP-dependent DEAD-box RNA helicase p72. Mol. Cell. Biol. 22, 5698–5707 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kar, A. et al. RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5′ splice site. Mol. Cell. Biol. 31, 1812–1821 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Camats, M., Guil, S., Kokolo, M. & Bach-Elias, M. P68 RNA helicase (DDX5) alters activity of cis- and trans-acting factors of the alternative splicing of H-Ras. PLoS ONE 3, e2926 (2008).

    PubMed  PubMed Central  Google Scholar 

  21. Lin, C., Yang, L., Yang, J. J., Huang, Y. & Liu, Z. R. ATPase/helicase activities of p68 RNA helicase are required for pre-mRNA splicing but not for assembly of the spliceosome. Mol. Cell. Biol. 25, 7484–7493 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Auboeuf, D., Honig, A., Berget, S. M. & O'Malley, B. W. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298, 416–419 (2002).

    CAS  PubMed  Google Scholar 

  23. Dardenne, E. et al. RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep. 7, 1900–1913 (2014). A demonstration of a dynamic and coordinated regulation of gene expression programmes by DEAD-box helicases during cell differentiation.

    CAS  PubMed  Google Scholar 

  24. Wang, Z., Murigneux, V. & Le Hir, H. Transcriptome-wide modulation of splicing by the exon junction complex. Genome Biol. 15, 551 (2014).

    PubMed  PubMed Central  Google Scholar 

  25. Michelle, L. et al. Proteins associated with the exon junction complex also control the alternative splicing of apoptotic regulators. Mol. Cell. Biol. 32, 954–967 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Polprasert, C. et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27, 658–670 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ilagan, J. O., Chalkley, R. J., Burlingame, A. L. & Jurica, M. S. Rearrangements within human spliceosomes captured after exon ligation. RNA 19, 400–412 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Will, C. L. et al. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 21, 4978–4988 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Germain, D. R. et al. Loss of the Drosophila melanogaster DEAD box protein Ddx1 leads to reduced size and aberrant gametogenesis. Dev. Biol. 407, 232–245 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Burckin, T. et al. Exploring functional relationships between components of the gene expression machinery. Nat. Struct. Mol. Biol. 12, 175–182 (2005). An analysis of yeast components of transcription, splicing, mRNA export, translation and decay machineries, which highlights the coordination between the different steps.

    CAS  PubMed  Google Scholar 

  31. Koodathingal, P. & Staley, J. P. Splicing fidelity: DEAD/H-box ATPases as molecular clocks. RNA Biol. 10, 1073–1079 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chang, T. H., Tung, L., Yeh, F. L., Chen, J. H. & Chang, S. L. Functions of the DExD/H-box proteins in nuclear pre-mRNA splicing. Biochim. Biophys. Acta 1829, 764–774 (2013).

    CAS  PubMed  Google Scholar 

  33. Cordin, O. & Beggs, J. D. RNA helicases in splicing. RNA Biol. 10, 83–95 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Semlow, D. R. & Staley, J. P. Staying on message: ensuring fidelity in pre-mRNA splicing. Trends Biochem. Sci. 37, 263–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Semlow, D. R., Blanco, M. R., Walter, N. G. & Staley, J. P. Spliceosomal DEAH-Box ATPases remodel pre-mRNA to activate alternative splice sites. Cell 164, 985–998 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin, Y., Yang, Y. & Zhang, P. New insights into RNA secondary structure in the alternative splicing of pre-mRNAs. RNA Biol. 8, 450–457 (2011).

    CAS  PubMed  Google Scholar 

  37. Wickramasinghe, V. O. & Laskey, R. A. Control of mammalian gene expression by selective mRNA export. Nat. Rev. Mol. Cell Biol. 16, 431–442 (2015).

    CAS  PubMed  Google Scholar 

  38. Le Hir, H., Sauliere, J. & Wang, Z. The exon junction complex as a node of post-transcriptional networks. Nat. Rev. Mol. Cell Biol. 17, 41–54 (2016).

    PubMed  Google Scholar 

  39. Sauliere, J. et al. CLIP-seq of eIF4AIII reveals transcriptome-wide mapping of the human exon junction complex. Nat. Struct. Mol. Biol. 19, 1124–1131 (2012).

    CAS  PubMed  Google Scholar 

  40. Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647 (2001).

    CAS  PubMed  Google Scholar 

  41. Tieg, B. & Krebber, H. Dbp5 — from nuclear export to translation. Biochim. Biophys. Acta 1829, 791–798 (2013).

    CAS  PubMed  Google Scholar 

  42. Yamazaki, T. et al. The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression. Mol. Biol. Cell 21, 2953–2965 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sheng, Y., Tsai-Morris, C. H., Gutti, R., Maeda, Y. & Dufau, M. L. Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is a transport protein involved in gene-specific mRNA export and protein translation during spermatogenesis. J. Biol. Chem. 281, 35048–35056 (2006).

    CAS  PubMed  Google Scholar 

  44. Smillie, D. A. & Sommerville, J. RNA helicase p54 (DDX6) is a shuttling protein involved in nuclear assembly of stored mRNP particles. J. Cell Sci. 115, 395–407 (2002).

    CAS  PubMed  Google Scholar 

  45. Lai, M. C., Lee, Y. H. & Tarn, W. Y. The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol. Biol. Cell 19, 3847–3858 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yedavalli, V. S., Neuveut, C., Chi, Y. H., Kleiman, L. & Jeang, K. T. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function. Cell 119, 381–392 (2004).

    CAS  PubMed  Google Scholar 

  47. Huang, F. et al. RNA helicase MOV10 functions as a co-factor of HIV-1 Rev to facilitate Rev/RRE-dependent nuclear export of viral mRNAs. Virology 486, 15–26 (2015).

    CAS  PubMed  Google Scholar 

  48. Yasuda-Inoue, M., Kuroki, M. & Ariumi, Y. Distinct, D. D. X. DEAD-box RNA helicases cooperate to modulate the HIV-1 Rev function. Biochem. Biophys. Res. Commun. 434, 803–808 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Reddy, T. R., Tang, H., Xu, W. & Wong-Staal, F. Sam68, RNA helicase A and Tap cooperate in the post-transcriptional regulation of human immunodeficiency virus and type D retroviral mRNA. Oncogene 19, 3570–3575 (2000).

    CAS  PubMed  Google Scholar 

  50. Choe, J. et al. eIF4AIII enhances translation of nuclear cap-binding complex-bound mRNAs by promoting disruption of secondary structures in 5′UTR. Proc. Natl Acad. Sci. USA 111, E4577–E4586 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Modelska, A. et al. The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell Death Dis. 6, e1603 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Fukao, A. et al. MicroRNAs trigger dissociation of eIF4AI and eIF4AII from target mRNAs in humans. Mol. Cell 56, 79–89 (2014).

    CAS  PubMed  Google Scholar 

  55. Rubio, C. A. et al. Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 15, 476 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. Wolfe, A. L. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70 (2014). Genome-wide analysis that identifies highly stable G-quadruplex structures as a hallmark of the 5′ UTRs of DDX2-targeted mRNAs.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sen, N. D., Zhou, F., Ingolia, N. T. & Hinnebusch, A. G. Genome-wide analysis of translational efficiency reveals distinct but overlapping functions of yeast DEAD-box RNA helicases Ded1 and eIF4A. Genome Res. 25, 1196–1205 (2015). A genome-wide analysis of transcripts revealing that Ded1-specific mRNA targets tend to have long, structured 5′UTRs.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen, H. H., Yu, H. I., Cho, W. C. & Tarn, W. Y. DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene 34, 2790–2800 (2015).

    CAS  PubMed  Google Scholar 

  59. Soto-Rifo, R. et al. DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J. 31, 3745–3756 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lai, M. C., Chang, W. C., Shieh, S. Y. & Tarn, W. Y. DDX3 regulates cell growth through translational control of cyclin E1. Mol. Cell. Biol. 30, 5444–5453 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Dhote, V., Sweeney, T. R., Kim, N., Hellen, C. U. & Pestova, T. V. Roles of individual domains in the function of DHX29, an essential factor required for translation of structured mammalian mRNAs. Proc. Natl Acad. Sci. USA 109, E3150–E3159 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Parsyan, A. et al. The helicase protein DHX29 promotes translation initiation, cell proliferation, and tumorigenesis. Proc. Natl Acad. Sci. USA 106, 22217–22222 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Giorgi, C. et al. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 130, 179–191 (2007).

    CAS  PubMed  Google Scholar 

  65. Li, Q. et al. Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII. Mol. Cell. Biol. 19, 7336–7346 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Halaby, M. J., Harris, B. R., Miskimins, W. K., Cleary, M. P. & Yang, D. Q. Deregulation of internal ribosome entry site-mediated p53 translation in cancer cells with defective p53 response to DNA damage. Mol. Cell. Biol. 35, 4006–4017 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Halaby, M. J. et al. Translational control protein 80 stimulates IRES-mediated translation of p53 mRNA in response to DNA damage. Biomed. Res. Int. 2015, 708158 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Manojlovic, Z. & Stefanovic, B. A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs. RNA 18, 321–334 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Peng, S. et al. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells 29, 496–504 (2011).

    CAS  PubMed  Google Scholar 

  70. Zhang, Y., You, J., Wang, X. & Weber, J. The DHX33 RNA helicase promotes mRNA translation initiation. Mol. Cell. Biol. 35, 2918–2931 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yajima, M. & Wessel, G. M. Essential elements for translation: the germline factor Vasa functions broadly in somatic cells. Development 142, 1960–1970 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ferguson, S. B., Blundon, M. A., Klovstad, M. S. & Schupbach, T. Modulation of gurken translation by insulin and TOR signaling in Drosophila. J. Cell Sci. 125, 1407–1419 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Johnstone, O. & Lasko, P. Interaction with eIF5B is essential for Vasa function during development. Development 131, 4167–4178 (2004).

    CAS  PubMed  Google Scholar 

  74. Gross, T. et al. The DEAD-box RNA helicase Dbp5 functions in translation termination. Science 315, 646–649 (2007).

    CAS  PubMed  Google Scholar 

  75. Wang, Y., Arribas-Layton, M., Chen, Y., Lykke-Andersen, J. & Sen, G. L. DDX6 orchestrates mammalian progenitor function through the mRNA degradation and translation pathways. Mol. Cell 60, 118–130 (2015). A demonstration that different DDX6-containing complexes confer different fates (either degradation or translation) to specific mRNA subsets.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tsai-Morris, C. H., Sato, H., Gutti, R. & Dufau, M. L. Role of gonadotropin regulated testicular RNA helicase (GRTH/Ddx25) on polysomal associated mRNAs in mouse testis. PLoS ONE 7, e32470 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Siwaszek, A., Ukleja, M. & Dziembowski, A. Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model systems. RNA Biol. 11, 1122–1136 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Fischer, N. & Weis, K. The DEAD box protein Dhh1 stimulates the decapping enzyme Dcp1. EMBO J. 21, 2788–2797 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Coller, J. M., Tucker, M., Sheth, U., Valencia-Sanchez, M. A. & Parker, R. The DEAD box helicase, Dhh1p, functions in mRNA decapping and interacts with both the decapping and deadenylase complexes. RNA 7, 1717–1727 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hu, G. et al. A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy. Nat. Cell Biol. 17, 930–942 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Johnson, S. J. & Jackson, R. N. Ski2-like RNA helicase structures: common themes and complex assemblies. RNA Biol. 10, 33–43 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tran, H., Schilling, M., Wirbelauer, C., Hess, D. & Nagamine, Y. Facilitation of mRNA deadenylation and decay by the exosome-bound, DExH protein RHAU. Mol. Cell 13, 101–111 (2004).

    CAS  PubMed  Google Scholar 

  83. Lykke-Andersen, S. & Jensen, T. H. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat. Rev. Mol. Cell Biol. 16, 665–677 (2015).

    CAS  PubMed  Google Scholar 

  84. Fiorini, F., Bagchi, D., Le Hir, H. & Croquette, V. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities. Nat. Commun. 6, 7581 (2015). An in vitro study that demonstrates the capacity of UPF1 to translocate through long and structured nucleic acids and to displace associated proteins.

    PubMed  Google Scholar 

  85. Gregersen, L. H. et al. MOV10 is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Mol. Cell 54, 573–585 (2014).

    CAS  PubMed  Google Scholar 

  86. Hug, N. & Caceres, J. F. The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex. Cell Rep. 8, 1845–1856 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Geissler, V., Altmeyer, S., Stein, B., Uhlmann-Schiffler, H. & Stahl, H. The RNA helicase Ddx5/p68 binds to hUpf3 and enhances NMD of Ddx17/p72 and Smg5 mRNA. Nucleic Acids Res. 41, 7875–7888 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bond, A. T., Mangus, D. A., He, F. & Jacobson, A. Absence of Dbp2p alters both nonsense-mediated mRNA decay and rRNA processing. Mol. Cell. Biol. 21, 7366–7379 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Jonas, S. & Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421–433 (2015).

    CAS  PubMed  Google Scholar 

  90. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  91. Motino, O. et al. Regulation of microRNA 183 by cyclooxygenase 2 in liver is DEAD-box helicase p68 (DDX5) dependent: role in insulin signaling. Mol. Cell. Biol. 35, 2554–2567 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Moy, R. H. et al. Stem-loop recognition by DDX17 facilitates miRNA processing and antiviral defense. Cell 158, 764–777 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Mori, M. et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 156, 893–906 (2014). Rare evidence that a DEAD-box RNA helicase can bind to its RNA targets in a sequence-specific manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, D., Huang, J. & Hu, Z. RNA helicase DDX5 regulates microRNA expression and contributes to cytoskeletal reorganization in basal breast cancer cells. Mol. Cell. Proteomics 11, M111.011932 (2012).

    PubMed  Google Scholar 

  95. Suzuki, H. I. et al. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009).

    CAS  PubMed  Google Scholar 

  96. Kawai, S. & Amano, A. BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. J. Cell Biol. 197, 201–208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Han, C. et al. The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep. 8, 1447–1460 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).

    CAS  PubMed  Google Scholar 

  99. Yin, J. et al. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain 138, 2553–2570 (2015).

    PubMed  Google Scholar 

  100. Dai, L. et al. Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region: implications of its role in germ cell development. J. Biol. Chem. 286, 44306–44318 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Krol, J. et al. A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture. Nat. Commun. 6, 7305 (2015).

    CAS  PubMed  Google Scholar 

  102. Bicker, S. et al. The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134. Genes Dev. 27, 991–996 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Salzman, D. W., Shubert-Coleman, J. & Furneaux, H. P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression. J. Biol. Chem. 282, 32773–32779 (2007).

    CAS  PubMed  Google Scholar 

  104. Takata, A. et al. A miRNA machinery component DDX20 controls NF-κB via microRNA-140 function. Biochem. Biophys. Res. Commun. 420, 564–569 (2012).

    CAS  PubMed  Google Scholar 

  105. Robb, G. B. & Rana, T. M. RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol. Cell 26, 523–537 (2007).

    CAS  PubMed  Google Scholar 

  106. Kasim, V., Wu, S., Taira, K. & Miyagishi, M. Determination of the role of DDX3 a factor involved in mammalian RNAi pathway using an shRNA-expression library. PLoS ONE 8, e59445 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Poulton, J. S. et al. The microRNA pathway regulates the temporal pattern of Notch signaling in Drosophila follicle cells. Development 138, 1737–1745 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ulvila, J. et al. Double-stranded RNA is internalized by scavenger receptor-mediated endocytosis in Drosophila S2 cells. J. Biol. Chem. 281, 14370–14375 (2006).

    CAS  PubMed  Google Scholar 

  109. Kenny, P. J. et al. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 9, 1729–1741 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Meijer, H. A. et al. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340, 82–85 (2013).

    CAS  PubMed  Google Scholar 

  111. Hooper, C. & Hilliker, A. Packing them up and dusting them off: RNA helicases and mRNA storage. Biochim. Biophys. Acta 1829, 824–834 (2013).

    CAS  PubMed  Google Scholar 

  112. Hilliker, A. Analysis of RNA helicases in P-bodies and stress granules. Methods Enzymol. 511, 323–346 (2012).

    CAS  PubMed  Google Scholar 

  113. Pimentel, J. & Boccaccio, G. L. Translation and silencing in RNA granules: a tale of sand grains. Front. Mol. Neurosci. 7, 68 (2014).

    PubMed  PubMed Central  Google Scholar 

  114. Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513–525 (2004).

    CAS  PubMed  Google Scholar 

  115. Buxbaum, A. R., Haimovich, G. & Singer, R. H. In the right place at the right time: visualizing and understanding mRNA localization. Nat. Rev. Mol. Cell Biol. 16, 95–109 (2015).

    CAS  PubMed  Google Scholar 

  116. Presnyak, V. & Coller, J. The DHH1/RCKp54 family of helicases: an ancient family of proteins that promote translational silencing. Biochim. Biophys. Acta 1829, 817–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Weston, A. & Sommerville, J. Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation. Nucleic Acids Res. 34, 3082–3094 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nagamori, I., Cruickshank, V. A. & Sassone-Corsi, P. Regulation of an RNA granule during spermatogenesis: acetylation of MVH in the chromatoid body of germ cells. J. Cell Sci. 124, 4346–4355 (2011).

    CAS  PubMed  Google Scholar 

  119. Gustafson, E. A. & Wessel, G. M. Vasa genes: emerging roles in the germ line and in multipotent cells. Bioessays 32, 626–637 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Beckham, C. et al. The DEAD-box RNA helicase Ded1p affects and accumulates in Saccharomyces cerevisiae P-bodies. Mol. Biol. Cell 19, 984–993 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Johnstone, O. et al. Belle is a Drosophila DEAD-box protein required for viability and in the germ line. Dev. Biol. 277, 92–101 (2005).

    CAS  PubMed  Google Scholar 

  122. Tsai-Morris, C. H., Sheng, Y., Gutti, R. K., Tang, P. Z. & Dufau, M. L. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25): a multifunctional protein essential for spermatogenesis. J. Androl. 31, 45–52 (2010).

    CAS  PubMed  Google Scholar 

  123. Vessey, J. P. et al. An asymmetrically localized Staufen2-dependent RNA complex regulates maintenance of mammalian neural stem cells. Cell Stem Cell 11, 517–528 (2012).

    CAS  PubMed  Google Scholar 

  124. Todd, A. G. et al. SMN, Gemin2 and Gemin3 associate with β-actin mRNA in the cytoplasm of neuronal cells in vitro. J. Mol. Biol. 401, 681–689 (2010).

    CAS  PubMed  Google Scholar 

  125. Irion, U. & Leptin, M. Developmental and cell biological functions of the Drosophila DEAD-box protein abstrakt. Curr. Biol. 9, 1373–1381 (1999).

    CAS  PubMed  Google Scholar 

  126. Meignin, C. & Davis, I. UAP56 RNA helicase is required for axis specification and cytoplasmic mRNA localization in Drosophila. Dev. Biol. 315, 89–98 (2008).

    CAS  PubMed  Google Scholar 

  127. Banerjee, S., Neveu, P. & Kosik, K. S. A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation. Neuron 64, 871–884 (2009).

    CAS  PubMed  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Stutz, F. & Izaurralde, E. The interplay of nuclear mRNP assembly, mRNA surveillance and export. Trends Cell Biol. 13, 319–327 (2003).

    CAS  PubMed  Google Scholar 

  130. Cullen, B. R. Nuclear RNA export. J. Cell Sci. 116, 587–597 (2003).

    PubMed  Google Scholar 

  131. Maniatis, T. & Reed, R. An extensive network of coupling among gene expression machines. Nature 416, 499–506 (2002).

    CAS  PubMed  Google Scholar 

  132. Calo, E. et al. RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. Nature 518, 249–253 (2015). A clear demonstration that an RNA helicase can coordinate different gene expression steps.

    CAS  PubMed  Google Scholar 

  133. Wu, C. Y., Tsai, Y. P., Wu, M. Z., Teng, S. C. & Wu, K. J. Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. Trends Genet. 28, 454–463 (2012).

    CAS  PubMed  Google Scholar 

  134. Dufu, K. et al. ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex. Genes Dev. 24, 2043–2053 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Hautbergue, G. M., Hung, M. L., Golovanov, A. P., Lian, L. Y. & Wilson, S. A. Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc. Natl Acad. Sci. USA 105, 5154–5159 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Steckelberg, A. L., Altmueller, J., Dieterich, C. & Gehring, N. H. CWC22-dependent pre-mRNA splicing and eIF4A3 binding enables global deposition of exon junction complexes. Nucleic Acids Res. 43, 4687–4700 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Alexandrov, A., Colognori, D., Shu, M. D. & Steitz, J. A. Human spliceosomal protein CWC22 plays a role in coupling splicing to exon junction complex deposition and nonsense-mediated decay. Proc. Natl Acad. Sci. USA 109, 21313–21318 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Barbosa, I. et al. Human CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly. Nat. Struct. Mol. Biol. 19, 983–990 (2012).

    CAS  PubMed  Google Scholar 

  139. Ballut, L. et al. The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity. Nat. Struct. Mol. Biol. 12, 861–869 (2005). The first demonstration that an RNA helicase (DDX48) can lock an RNP (the EJC) on its target RNA.

    CAS  PubMed  Google Scholar 

  140. Ohno, M. & Shimura, Y. A human RNA helicase-like protein, HRH1, facilitates nuclear export of spliced mRNA by releasing the RNA from the spliceosome. Genes Dev. 10, 997–1007 (1996).

    CAS  PubMed  Google Scholar 

  141. Ma, W. K., Cloutier, S. C. & Tran, E. J. The DEAD-box protein Dbp2 functions with the RNA-binding protein Yra1 to promote mRNP assembly. J. Mol. Biol. 425, 3824–3838 (2013). This study shows that co-transcriptional mRNP assembly requires Dbp2 unwinding activity; once the mRNP is assembled, Dbp2 inhibition by the adaptor Yra1 prevents further rearrangements of the nuclear mRNP so that it can be exported.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zonta, E. et al. The RNA helicase DDX5/p68 is a key factor promoting c-fos expression at different levels from transcription to mRNA export. Nucleic Acids Res. 41, 554–564 (2013).

    CAS  PubMed  Google Scholar 

  143. Choi, Y. J. & Lee, S. G. The DEAD-box RNA helicase DDX3 interacts with DDX5, co-localizes with it in the cytoplasm during the G2/M phase of the cycle, and affects its shuttling during mRNP export. J. Cell Biochem. 113, 985–996 (2012).

    CAS  PubMed  Google Scholar 

  144. Sharma, D. & Jankowsky, E. The Ded1/DDX3 subfamily of DEAD-box RNA helicases. Crit. Rev. Biochem. Mol. Biol. 49, 343–360 (2014).

    CAS  PubMed  Google Scholar 

  145. Soto-Rifo, R. & Ohlmann, T. The role of the DEAD-box RNA helicase DDX3 in mRNA metabolism. Wiley Interdiscip. Rev. RNA 4, 369–385 (2013).

    CAS  PubMed  Google Scholar 

  146. Senissar, M. et al. The DEAD-box helicase Ded1 from yeast is an mRNP cap-associated protein that shuttles between the cytoplasm and nucleus. Nucleic Acids Res. 42, 10005–10022 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Hauk, G. & Bowman, G. D. Formation of a trimeric Xpo1-Ran[GTP]-Ded1 exportin complex modulates ATPase and helicase activities of Ded1. PLoS ONE 10, e0131690 (2015). This study demonstrates that the binding of Ded1 to the export complex Xpo1–RanċGTP inhibits the enzymatic activity of the RNA helicase and prevents translation.

    PubMed  PubMed Central  Google Scholar 

  148. Hilliker, A., Gao, Z., Jankowsky, E. & Parker, R. The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex. Mol. Cell 43, 962–972 (2011). This paper shows that Ded1 transits through stress granules by the regulation of its ATPase activity, which controls its association with eIF4F.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Shih, J. W., Tsai, T. Y., Chao, C. H. & Wu Lee, Y. H. Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene 27, 700–714 (2008).

    CAS  PubMed  Google Scholar 

  150. Geissler, R., Golbik, R. P. & Behrens, S. E. The DEAD-box helicase DDX3 supports the assembly of functional 80S ribosomes. Nucleic Acids Res. 40, 4998–5011 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Chuang, R. Y., Weaver, P. L., Liu, Z. & Chang, T. H. Requirement of the DEAD-box protein Ded1p for messenger RNA translation. Science 275, 1468–1471 (1997).

    CAS  PubMed  Google Scholar 

  152. Bolger, T. A. & Wente, S. R. Gle1 is a multifunctional DEAD-box protein regulator that modulates Ded1 in translation initiation. J. Biol. Chem. 286, 39750–39759 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Huch, S. & Nissan, T. Interrelations between translation and general mRNA degradation in yeast. Wiley Interdiscip. Rev. RNA 5, 747–763 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Roy, B. & Jacobson, A. The intimate relationships of mRNA decay and translation. Trends Genet. 29, 691–699 (2013).

    CAS  PubMed  Google Scholar 

  155. Ostareck, D. H., Naarmann- de Vries, I. S. & Ostareck-Lederer, A. DDX6 and its orthologs as modulators of cellular and viral RNA expression. Wiley Interdiscip. Rev. RNA 5, 659–678 (2014).

    CAS  PubMed  Google Scholar 

  156. Rouya, C. et al. Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. RNA 20, 1398–1409 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Chen, Y. et al. A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing. Mol. Cell 54, 737–750 (2014).

    CAS  PubMed  Google Scholar 

  158. Mathys, H. et al. Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression. Mol. Cell 54, 751–765 (2014). Structural and biochemical analyses demonstrating the activation of the DDX6 ATPase activity by the CCR4–NOT complex, an important step for miRNA-mediated repression of gene expression.

    CAS  PubMed  Google Scholar 

  159. Nishihara, T., Zekri, L., Braun, J. E. & Izaurralde, E. miRISC recruits decapping factors to miRNA targets to enhance their degradation. Nucleic Acids Res. 41, 8692–8705 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Su, H. et al. Mammalian hyperplastic discs homolog EDD regulates miRNA-mediated gene silencing. Mol. Cell 43, 97–109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Nishimura, T. et al. The eIF4E-binding protein 4E-T is a component of the mRNA decay machinery that bridges the 5′ and 3′ termini of target mRNAs. Cell Rep. 11, 1425–1436 (2015). This study identifies the 4E-T protein as a key player in miRNA-mediated mRNA decay, as it potentially links the 3′ mRNA end and the DDX6-associated CCR4–NOT deadenylase complex to the cap-associated protein eIF4E.

    CAS  PubMed  Google Scholar 

  162. Ozgur, S. & Stoecklin, G. Role of Rck-Pat1b binding in assembly of processing-bodies. RNA Biol. 10, 528–539 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Eulalio, A. et al. Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. Genes Dev. 21, 2558–2570 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Makino, S., Mishima, Y., Inoue, K. & Inada, T. Roles of mRNA fate modulators Dhh1 and Pat1 in TNRC6-dependent gene silencing recapitulated in yeast. J. Biol. Chem. 290, 8331–8347 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Chu, C. Y. & Rana, T. M. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, e210 (2006).

    PubMed  PubMed Central  Google Scholar 

  166. Ozgur, S. et al. Structure of a human 4E-T/DDX6/CNOT1 complex reveals the different interplay of DDX6-binding proteins with the CCR4-NOT complex. Cell Rep. 13, 703–711 (2015).

    CAS  PubMed  Google Scholar 

  167. Fuller-Pace, F. V. & Moore, H. C. RNA helicases p68 and p72: multifunctional proteins with important implications for cancer development. Future Oncol. 7, 239–251 (2011).

    CAS  PubMed  Google Scholar 

  168. Abdelhaleem, M. RNA helicases: regulators of differentiation. Clin. Biochem. 38, 499–503 (2005).

    CAS  PubMed  Google Scholar 

  169. Coller, J. & Parker, R. General translational repression by activators of mRNA decapping. Cell 122, 875–886 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Liu, F., Putnam, A. A. & Jankowsky, E. DEAD-box helicases form nucleotide-dependent, long-lived complexes with RNA. Biochemistry 53, 423–433 (2014).

    CAS  PubMed  Google Scholar 

  171. Steimer, L. & Klostermeier, D. RNA helicases in infection and disease. RNA Biol. 9, 751–771 (2012).

    CAS  PubMed  Google Scholar 

  172. Pyle, A. M. Translocation and unwinding mechanisms of RNA and DNA helicases. Annu. Rev. Biophys. 37, 317–336 (2008).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge their colleagues and other collaborators whose findings contributed to this Review. They also apologize for uncited works owing to space limitations (more citations are provided in Supplementary information S1 (table)). The authors gratefully acknowledge the organizations that have funded their research over the past years, including the French Agence Nationale de la Recherche (ANR), INCa, AFM-Téléthon, Fondation ARC, FRM and LNCC. The authors are supported by INSERM (French National Institute of Health and Medical Research).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Didier Auboeuf.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Functional classification of RNA helicases (XLSX 48 kb)

PowerPoint slides

Glossary

RecA domains

Protein domains of RNA helicases that are named after the Escherichia coli homologous recombination protein RecA.

Argonaute

A family of proteins that bind to various non-coding RNAs, including microRNAs, and mediate RNA silencing.

Transport granules

Ribonucleoprotein particles containing mRNAs, RNA-binding proteins and motor proteins that are involved in mRNA cytoplasmic transport and localized mRNA translation.

Stress granules

Dense cytoplasmic structures that are enriched in mRNAs and proteins, which form under stress conditions to store translationally stalled mRNAs.

Heterogeneous nuclear ribonucleoprotein H and F (hnRNP H/F)

Proteins that bind to RNA containing guanosine-rich sequences and that have diverse functions in RNA metabolism, especially in the regulation of alternative splicing.

G-quadruplex

Highly stable nucleic acid structure formed in guanine (G)-rich regions by the stacking of at least two G-tetrads, each of them corresponding to a square-shaped association between four guanines.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bourgeois, C., Mortreux, F. & Auboeuf, D. The multiple functions of RNA helicases as drivers and regulators of gene expression. Nat Rev Mol Cell Biol 17, 426–438 (2016). https://doi.org/10.1038/nrm.2016.50

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2016.50

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing