Key Points
-
Global approaches are defining the full complement of proteins with RNA-binding capacity in living cells.
-
RNA packaging by proteins begins during transcription and determines the fate of the RNA.
-
RNA-binding proteins (RBPs) can act as 'molecular rulers', sorting RNAs according to their length.
-
RBPs can link sequential and non-sequential processing steps.
-
A future challenge is to define the composition of individual mRNPs at different stages of remodelling.
Abstract
mRNA is packaged into ribonucleoprotein particles called mRNPs. A multitude of RNA-binding proteins as well as a host of associated proteins participate in the fate of mRNA from transcription and processing in the nucleus to translation and decay in the cytoplasm. Methodological innovations in cell biology and genome-wide high-throughput approaches have revealed an unexpected diversity of mRNA-associated proteins and unforeseen interconnections between mRNA-processing steps. Recent insights into mRNP formation in vivo have also highlighted the importance of mRNP packaging, which can sort RNAs on the basis of their length and determine mRNA fate through alternative mRNP assembly, processing and export pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fischer, U., Englbrecht, C. & Chari, A. Biogenesis of spliceosomal small nuclear ribonucleoproteins. Wiley Interdiscip. Rev. RNA 2, 718–731 (2011).
Watkins, N. J. & Bohnsack, M. T. The box C/D and H/ACA snoRNPs: key players in the modification, processing and the dynamic folding of ribosomal RNA. Wiley Interdiscip. Rev. RNA 3, 397–414 (2012).
Keene, J. D. RNA regulons: coordination of post-transcriptional events. Nature Rev. Genet. 8, 533–543 (2007).
Ascano, M., Hafner, M., Cekan, P., Gerstberger, S. & Tuschl, T. Identification of RNA–protein interaction networks using PAR-CLIP. Wiley Interdiscip. Rev. RNA 3, 159–177 (2012).
Anko, M. L. & Neugebauer, K. M. RNA–protein interactions in vivo: global gets specific. Trends Biochem. Sci. 37, 255–262 (2012).
Moore, M. J. & Proudfoot, N. J. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688–700 (2009).
Schoenberg, D. R. & Maquat, L. E. Regulation of cytoplasmic mRNA decay. Nature Rev. Genet. 13, 246–259 (2012).
König, J., Zarnack, K., Luscombe, N. M. & Ule, J. Protein–RNA interactions: new genomic technologies and perspectives. Nature Rev. Genet. 13, 77–83 (2011).
Tutucci, E. & Stutz, F. Keeping mRNPs in check during assembly and nuclear export. Nature Rev. Mol. Cell Biol. 12, 377–384 (2011).
Grunwald, D. & Singer, R. H. Multiscale dynamics in nucleocytoplasmic transport. Curr. Opin. Cell Biol. 24, 100–106 (2012).
Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).
Baltz, A. G. et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012). References 11 and 12 introduce new methods to identify RNA-binding proteins globally in human cell lines, to provide a comprehensive atlas of proteins that can bind to polyadenylated RNAs and to identify novel RNA-binding domains.
Mitchell, S. F., Jain, S., She, M. & Parker, R. Global analysis of yeast mRNPs. Nature Struct. Mol. Biol. 20, 127–133 (2013).
Kishore, S., Luber, S. & Zavolan, M. Deciphering the role of RNA-binding proteins in the post-transcriptional control of gene expression. Brief. Funct. Genom. 9, 391–404 (2010).
Cui, X. A., Zhang, H. & Palazzo, A. F. p180 promotes the ribosome-independent localization of a subset of mRNA to the endoplasmic reticulum. PLoS Biol. 10, e1001336 (2012).
Mackereth, C. D. & Sattler, M. Dynamics in multi-domain protein recognition of RNA. Curr. Opin. Struct. Biol. 22, 287–296 (2012).
Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).
MacRae, I. J., Zhou, K. & Doudna, J. A. Structural determinants of RNA recognition and cleavage by Dicer. Nature Struct. Mol. Biol. 14, 934–940 (2007).
Lamichhane, R., Solem, A., Black, W. & Rueda, D. Single-molecule FRET of protein–nucleic acid and protein–protein complexes: surface passivation and immobilization. Methods 52, 192–200 (2010).
Konig, J. et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nature Struct. Mol. Biol. 17, 909–915 (2010). Introducing a new method to identify direct binding sites of RNA-binding proteins with a high resolution, termed iCLIP, the authors of this paper indicate that hnRNPC is crucial for the co-transcriptional packaging of most RNAs and provide a functional link to alternative splicing.
Kumar, A. & Pederson, T. Comparison of proteins bound to heterogeneous nuclear RNA and messenger RNA in HeLa cells. J. Mol. Biol. 96, 353–365 (1975).
Beyer, A. L., Christensen, M. E., Walker, B. W. & LeStourgeon, W. M. Identification and characterization of the packaging proteins of core 40S hnRNP particles. Cell 11, 127–138 (1977).
Derman, E., Goldberg, S. & Darnell, J. E. Jr. hnRNA in HeLa cells: distribution of transcript sizes estimated from nascent molecule profile. Cell 9, 465–472 (1976).
Mor, A. et al. Dynamics of single mRNP nucleocytoplasmic transport and export through the nuclear pore in living cells. Nature Cell Biol. 12, 543–552 (2010).
Gorlach, M., Burd, C. G., Portman, D. S. & Dreyfuss, G. The hnRNP proteins. Mol. Biol. Rep. 18, 73–78 (1993).
Dreyfuss, G., Choi, Y. D. & Adam, S. A. The ribonucleoprotein structures along the pathway of mRNA formation. Endocr. Res. 15, 441–474 (1989).
Weighardt, F., Biamonti, G. & Riva, S. The roles of heterogeneous nuclear ribonucleoproteins (hnRNP) in RNA metabolism. BioEssays 18, 747–756 (1996).
McAfee, J. G., Soltaninassab, S. R., Lindsay, M. E. & LeStourgeon, W. M. Proteins C1 and C2 of heterogeneous nuclear ribonucleoprotein complexes bind RNA in a highly cooperative fashion: support for their contiguous deposition on pre-mRNA during transcription. Biochemistry 35, 1212–1222 (1996).
McAfee, J. G., Shahied-Milam, L., Soltaninassab, S. R. & LeStourgeon, W. M. A major determinant of hnRNP C protein binding to RNA is a novel bZIP-like RNA binding domain. RNA 2, 1139–1152 (1996).
Huang, M. et al. The C-protein tetramer binds 230 to 240 nucleotides of pre-mRNA and nucleates the assembly of 40S heterogeneous nuclear ribonucleoprotein particles. Mol. Cell. Biol. 14, 518–533 (1994).
Neugebauer, K. M. Please hold—the next available exon will be right with you. Nature Struct. Mol. Biol. 13, 385–386 (2006).
Bentley, D. L. Rules of engagement: co-transcriptional recruitment of pre-mRNA processing factors. Curr. Opin. Cell Biol. 17, 251–256 (2005).
Listerman, I., Sapra, A. K. & Neugebauer, K. M. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nature Struct. Mol. Biol. 13, 815–822 (2006).
Wetterberg, I., Zhao, J., Masich, S., Wieslander, L. & Skoglund, U. In situ transcription and splicing in the Balbiani ring 3 gene. EMBO J. 20, 2564–2574 (2001).
Aguilera, A. & Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115–124 (2012).
Dye, M. J., Gromak, N. & Proudfoot, N. J. Exon tethering in transcription by RNA polymerase II. Mol. Cell 21, 849–859 (2006).
Martinez-Contreras, R. et al. hnRNP proteins and splicing control. Adv. Exp. Med. Biol. 623, 123–147 (2007).
Vargas, D. Y. et al. Single-molecule imaging of transcriptionally coupled and uncoupled splicing. Cell 147, 1054–1065 (2011).
McCloskey, A. Taniguchi, I., Shinmyozu, K. & Ohno, M. hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335, 1643–1646 (2012). This paper describes a new mechanism in which Pol II transcripts are sorted according to their length prior to nuclear export and identified hnRNPC as the key player.
Merz, C., Urlaub, H., Will, C. L. & Luhrmann, R. Protein composition of human mRNPs spliced in vitro and differential requirements for mRNP protein recruitment. RNA 13, 116–128 (2007).
Anko, M. L., Morales, L., Henry, I., Beyer, A. & Neugebauer, K. M. Global analysis reveals SRp20- and SRp75-specific mRNPs in cycling and neural cells. Nature Struct. Mol. Biol. 17, 962–970 (2010).
Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 750–764 (2012). This paper presents compelling evidence suggesting that the EJC and SR proteins cooperate in the packaging and compaction of mature mRNPs for efficient nuclear export.
Sauliere, J. et al. CLIP-seq of eIF4AIII reveals transcriptome-wide mapping of the human exon junction complex. Nature Struct. Mol. Biol. 19, 1124–1131 (2012).
Bjork, P. et al. Specific combinations of SR proteins associate with single pre-messenger RNAs in vivo and contribute different functions. J. Cell Biol. 184, 555–568 (2009).
Walsh, M. J., Hautbergue, G. M. & Wilson, S. A. Structure and function of mRNA export adaptors. Biochem. Soc. Trans. 38, 232–236 (2010).
Sapra, A. K. et al. SR protein family members display diverse activities in the formation of nascent and mature mRNPs in vivo. Mol. Cell 34, 179–190 (2009).
Lin, S., Xiao, R., Sun, P., Xu, X. & Fu, X. D. Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation. Mol. Cell 20, 413–425 (2005).
Caceres, J. F., Screaton, G. R. & Krainer, A. R. A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev. 12, 55–66 (1998).
Delestienne, N. et al. The splicing factor ASF/SF2 is associated with TIA-1-related/TIA-1-containing ribonucleoproteic complexes and contributes to post-transcriptional repression of gene expression. FEBS J. 277, 2496–2514 (2010).
Anko, M. L. et al. The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol. 13, R17 (2012).
Huang, Y. & Steitz, J. A. SRprises along a messenger's journey. Mol. Cell 17, 613–615 (2005).
Erkmann, J. A., Sanchez, R., Treichel, N., Marzluff, W. F. & Kutay, U. Nuclear export of metazoan replication-dependent histone mRNAs is dependent on RNA length and is mediated by TAP. RNA 11, 45–58 (2005).
Strasser, K. et al. TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417, 304–308 (2002).
Reed, R. & Cheng, H. TREX, SR proteins and export of mRNA. Curr. Opin. Cell Biol. 17, 269–273 (2005).
Dias, A. P., Dufu, K., Lei, H. & Reed, R. A role for TREX components in the release of spliced mRNA from nuclear speckle domains. Nature Commun. 1, 97 (2010).
Katahira, J., Inoue, H., Hurt, E. & Yoneda, Y. Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. EMBO J. 28, 556–567 (2009).
Lei, H., Dias, A. P. & Reed, R. Export and stability of naturally intronless mRNAs require specific coding region sequences and the TREX mRNA export complex. Proc. Natl Acad. Sci. USA 108, 17985–17990 (2011).
Palazzo, A. F. et al. The signal sequence coding region promotes nuclear export of mRNA. PLoS Biol. 5, e322 (2007).
Palazzo, A. F. & Akef, A. Nuclear export as a key arbiter of 'mRNA identity' in eukaryotes. Biochim. Biophys. Acta 1819, 566–577 (2012).
Cheng, H. et al. Human mRNA export machinery recruited to the 5′ end of mRNA. Cell 127, 1389–1400 (2006).
Nojima, T., Hirose, T., Kimura, H. & Hagiwara, M. The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export. J. Biol. Chem. 282, 15645–15651 (2007).
Sullivan, K. D., Mullen, T. E., Marzluff, W. F. & Wagner, E. J. Knockdown of SLBP results in nuclear retention of histone mRNA. RNA 15, 459–472 (2009).
Narita, T. et al. NELF interacts with CBC and participates in 3′ end processing of replication-dependent histone mRNAs. Mol. Cell 26, 349–365 (2007).
Wickramasinghe, V. O. et al. mRNA export from mammalian cell nuclei is dependent on GANP. Curr. Biol. 20, 25–31 (2010).
Jani, D. et al. Functional and structural characterization of the mammalian TREX-2 complex that links transcription with nuclear messenger RNA export. Nucleic Acids Res. 40, 4562–4573 (2012).
Proudfoot, N. J. Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770–1782 (2011).
Lou, H., Neugebauer, K. M., Gagel, R. F. & Berget, S. M. Regulation of alternative polyadenylation by U1 snRNPs and SRp20. Mol. Cell. Biol. 18, 4977–4985 (1998).
Berg, M. G. et al. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150, 53–64 (2012). This paper establishes U1 snRNP as a molecular ruler and describes how U1 snRNP levels influence the length of transcripts through suppression of PCPA. The authors demonstrate the physiological importance of this role of U1 snRNP in activated neurons.
Kaida, D. et al. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468, 664–668 (2010). In this study, the authors discovered a new splicing-independent function of U1 snRNP as a suppressor of alternative polyadenylation. The authors show that U1 snRNP protects pre-mRNAs from PCPA by binding to inappropriate poly(A) sites present within introns of pre-mRNAs.
Eckmann, C. R., Rammelt, C. & Wahle, E. Control of poly(A) tail length. Wiley Interdiscip. Rev. RNA 2, 348–361 (2011).
Keller, R. W. et al. The nuclear poly(A) binding protein, PABP2, forms an oligomeric particle covering the length of the poly(A) tail. J. Mol. Biol. 297, 569–583 (2000).
Lemay, J.-F., Lemieux, C., St-André, O. & Bachand, F. Crossing the borders: poly(A)-binding proteins working on both sides of the fence. RNA Biol. 7, 291–295 (2010).
Jenal, M. et al. The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149, 538–553 (2012). This work identified the nuclear poly(A)-binding protein PABPN1 as a potent suppressor of alternative polyadenylation and revealed the importance of APA in the pathology of a human disease caused by changes in PABPN1 levels.
Martin, G., Gruber, A. R., Keller, W. & Zavolan, M. Genome-wide analysis of pre-mRNA 3′ end processing reveals a decisive role of human cleavage factor I in the regulation of 3′ UTR length. Cell Rep. 1, 753–763 (2012).
Ruepp, M. D. Schümperli, D. & Barabino, S.M. mRNA 3′ end processing and more—multiple functions of mammalian cleavage factor I-68. Wiley Interdiscip. Rev. RNA 2, 79–91 (2011).
Lykke-Andersen, S., Brodersen, D. E. & Jensen, T. H. Origins and activities of the eukaryotic exosome. J. Cell Sci. 122, 1487–1494 (2009).
Butler, J. S. & Mitchell, P. Rrp6, Rrp47 and cofactors of the nuclear exosome. Adv. Exp. Med. Biol. 702, 91–104 (2010).
Lemay, J. F. et al. The nuclear poly(A)-binding protein interacts with the exosome to promote synthesis of noncoding small nucleolar RNAs. Mol. Cell 37, 34–45 (2010).
Lubas, M. et al. Interaction profiling identifies the human nuclear exosome targeting complex. Mol. Cell 43, 624–637 (2011).
Shcherbik, N., Wang, M., Lapik, Y. R. Srivastava, L. & Pestov, D. G. Polyadenylation and degradation of incomplete RNA polymerase I transcripts in mammalian cells. EMBO Rep. 11, 106–111 (2010).
Guo, T. B. et al. Spermatogenetic expression of RNA-binding motif protein 7, a protein that interacts with splicing factors. J. Androl. 24, 204–214 (2003).
Nag, A. & Steitz, J. A. Tri-snRNP-associated proteins interact with subunits of the TRAMP and nuclear exosome complexes, linking RNA decay and pre-mRNA splicing. RNA Biol. 9, 334–342 (2012).
Ni, J. Z. et al. Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev. 21, 708–718 (2007).
Lareau, L. F., Inada, M., Green, R. E., Wengrod, J. C. & Brenner, S. E. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446, 926–929 (2007).
Sureau, A., Gattoni, R., Dooghe, Y., Stevenin, J. & Soret, J. SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J. 20, 1785–1796 (2001).
Jumaa, H. & Nielsen, P. J. The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J. 16, 5077–5085 (1997).
Sun, S., Zhang, Z., Sinha, R., Karni, R. & Krainer, A. R. SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control. Nature Struct. Mol. Biol. 17, 306–312 (2010).
Conti, E. & Izaurralde, E. Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr. Opin. Cell Biol. 17, 316–325 (2005).
Zhang, Z. & Krainer, A. R. Involvement of SR proteins in mRNA surveillance. Mol. Cell 16, 597–607 (2004).
Sato, H., Hosoda, N. & Maquat, L. E. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol. Cell 29, 255–262 (2008).
Muhlemann, O. & Lykke-Andersen, J. How and where are nonsense mRNAs degraded in mammalian cells? RNA Biol. 7, 28–32 (2010).
Sun, M. et al. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation. Genome Res. 22, 1350–1359 (2012).
Dori-Bachash, M., Shema, E. & Tirosh, I. Coupled evolution of transcription and mRNA degradation. PLoS Biol. 9, e1001106 (2011).
Trcek, T., Larson, D. R., Moldon, A., Query, C. C. & Singer, R. H. Single-molecule mRNA decay measurements reveal promoter- regulated mRNA stability in yeast. Cell 147, 1484–1497 (2011). Using single-cell single molecule techniques, this study demonstrates for the first time a direct link between nuclear transcription and cytoplasmic mRNA stability.
Bregman, A. et al. Promoter elements regulate cytoplasmic mRNA decay. Cell 147, 1473–1483 (2011).
Heym, R. G. & Niessing, D. Principles of mRNA transport in yeast. Cell. Mol. Life Sci. 69, 1843–1853 (2012).
Shen, Z., St-Denis, A. & Chartrand, P. Cotranscriptional recruitment of She2p by RNA pol II elongation factor Spt4-Spt5/DSIF promotes mRNA localization to the yeast bud. Genes Dev. 24, 1914–1926 (2010).
Shen, Z., Paquin, N., Forget, A. & Chartrand, P. Nuclear shuttling of She2p couples ASH1 mRNA localization to its translational repression by recruiting Loc1p and Puf6p. Mol. Biol. Cell 20, 2265–2275 (2009).
Long, R. M., Gu, W., Lorimer, E., Singer, R. H. & Chartrand, P. She2p is a novel RNA-binding protein that recruits the Myo4p-She3p complex to ASH1 mRNA. EMBO J. 19, 6592–6601 (2000).
Gu, W., Pan, F., Zhang, H., Bassell, G. J. & Singer, R. H. A predominantly nuclear protein affecting cytoplasmic localization of β-actin mRNA in fibroblasts and neurons. J. Cell Biol. 156, 41–51 (2002).
Pan, F., Huttelmaier, S., Singer, R. H. & Gu, W. ZBP2 facilitates binding of ZBP1 to β-actin mRNA during transcription. Mol. Cell. Biol. 27, 8340–8351 (2007).
Hachet, O. & Ephrussi, A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428, 959–963 (2004).
Ghosh, S., Marchand, V., Gaspar, I. & Ephrussi, A. Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA. Nature Struct. Mol. Biol. 19, 441–449 (2012). This paper provides a mechanistic link between nuclear splicing and localized translation of oskar mRNA in the cytoplasm.
Trcek, T. & Singer, R. H. The cytoplasmic fate of an mRNP is determined cotranscriptionally: exception or rule? Genes Dev. 24, 1827–1831 (2010).
Viphakone, N. et al. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nature Commun. 3, 1006 (2012).
Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).
Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).
Klug, S. J. & Famulok, M. All you wanted to know about SELEX. Mol. Biol. Rep. 20, 97–107 (1994).
Martin, F. Fifteen years of the yeast three-hybrid system: RNA–protein interactions under investigation. Methods 58, 367–375 (2012).
Niranjanakumari, S., Lasda, E., Brazas, R. & Garcia-Blanco, M. A. Reversible cross-linking combined with immunoprecipitation to study RNA-protein interactions in vivo. Methods 26, 182–190 (2002).
Keene, J. D., Komisarow, J. M. & Friedersdorf, M. B. RIP-chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts. Nature Protoc. 1, 302–307 (2006).
Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464–469 (2008).
Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129–141 (2010).
Kishore, S. et al. A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins. Nature Methods 8, 559–564 (2011).
Kudla, G., Granneman, S., Hahn, D., Beggs, J. D. & Tollervey, D. Cross-linking, ligation, and sequencing of hybrids reveals RNA–RNA interactions in yeast. Proc. Natl Acad. Sci. USA 108, 10010–10015 (2011).
Speese, S. D. et al. Nuclear envelope budding enables large ribonucleoprotein particle export during synaptic Wnt signaling. Cell 149, 832–846 (2012).
Wu, C. H. et al. NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila. Genes Dev. 17, 1402–1414 (2003).
Gruber, J. J. et al. Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation. Cell 138, 328–339 (2009).
Gruber, J. J. et al. Ars2 promotes proper replication-dependent histone mRNA 3′ end formation. Mol. Cell 45, 87–98 (2012).
Lahudkar, S. et al. The mRNA cap-binding complex stimulates the formation of pre-initiation complex at the promoter via its interaction with Mot1p in vivo. Nucleic Acids Res. 39, 2188–2209 (2011).
Marzluff, W. F., Wagner, E. J. & Duronio, R. J. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nature Rev. Genet. 9, 843–854 (2008).
Maquat, L. E., Hwang, J., Sato, H. & Tang, Y. CBP80-promoted mRNP rearrangements during the pioneer round of translation, nonsense-mediated mRNA decay, and thereafter. Cold Spring Harb. Symp. Quant. Biol. 75, 127–134 (2010).
Visa, N., Izaurralde, E., Ferreira, J., Daneholt, B. & Mattaj, I. W. A nuclear cap-binding complex binds Balbiani ring pre-mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export. J. Cell Biol. 133, 5–14 (1996).
Katahira, J. mRNA export and the TREX complex. Biochim. Biophys. Acta 1819, 507–513 (2012).
Hautbergue, G. M. et al. UIF, a new mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr. Biol. 19, 1918–1924 (2009).
Ruepp, M. D. et al. Mammalian pre-mRNA 3′ end processing factor CF Im68 functions in mRNA export. Mol. Biol. Cell 20, 5211–5223 (2009).
Huang, Y., Gattoni, R., Stévenin, J. & Steitz, J. A. S. R. Splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837–843 (2003).
Acknowledgements
We thank members of our laboratory, T. Pederson and F. McNicoll for helpful discussions and comments on the manuscript. Work in our laboratory on mRNPs is supported by funding from the Max Planck Society and the German Research Foundation (NE-909/3-1 to K.M.N.), and long-term postdoctoral fellowships from the European Molecular Biology Organization (EMBO) and Fonds de recherche en santé du Québec (FRSQ; to M.M.-M.).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
FURTHER INFORMATION
Glossary
- Messenger ribonucleoprotein particles
-
(mRNPs). Complexes composed of mature mRNAs bound by various RNA-binding proteins and associated proteins recruited via protein–protein interactions. The formation of mRNPs allows proper packaging of the mRNA, which is essential for efficient nuclear export.
- 5′ end capping
-
As soon as a nascent transcript emerges from RNA polymerase II during transcription, it is capped at its 5′ end. This 7-methylguanosine cap (m7G cap) protects the mRNA from degradation and is essential for its translation.
- Peptidyl-prolyl-isomerases
-
(PPIs). A group of metabolic enzymes that catalyse the cis–trans isomerization of peptide bonds in polypeptide chains. PPIs have important roles in the folding of newly synthesized proteins but were recently shown also to bind mRNAs.
- RNA recognition motif
-
(RRM). One of the most abundant RNA-binding domains in eukaryotes.
- Spliceosome
-
A ribonucleoprotein complex that is responsible for splicing nuclear precursor mRNA (pre-mRNA). It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNP proteins, which recognize and assemble on exon–intron boundaries to catalyse intron removal from the precursor mRNA (pre-mRNA).
- Dicer
-
An RNase III family endonuclease that processes double-stranded RNA and precursor microRNAs into small interfering RNAs and microRNAs, respectively.
- Heterogeneous nuclear ribonucleoprotein particles
-
(hnRNPs). Complexes of newly synthesized precursor mRNA (pre-mRNA) and RNA-binding proteins, known as heterogeneous ribonucleoproteins, which form during transcription in the cell nucleus. The abundant hnRNP proteins regulate splicing and mark the RNA as immature. After splicing has occurred, the hnRNP proteins mainly remain bound to spliced introns.
- Premature cleavage and polyadenylation
-
(PCA). Misprocessing of precursor mRNAs (pre-mRNA) by the cleavage and polyadenylation machinery. Truncated transcripts arise through the use of cryptic or inappropriate polyadenylation signals present at the 5′ end or within introns of the pre-mRNA.
- R loops
-
Hybrid structures consisting of RNA and DNA in which RNA displaces a DNA strand to hybridize to its complementary DNA sequence.
- Exon junction complex
-
(EJC). A protein complex that is deposited ~24 nucleotides upstream of the exon–exon junctions of newly synthesized, spliced mRNAs. The EJC contains four core proteins — eukaryotic initiation factor 4AIII (EIF4AIII), Y14, mago nashi homologue (MAGOH) and Barentsz (BTZ) — and several loosely associated proteins.
- SR proteins
-
Evolutionarily conserved RNA-binding proteins with essential functions in precursor mRNA (pre-mRNA) splicing in metazoans. Individual SR proteins have distinct RNA-binding capacities and are important regulators of alternative splicing, while some also function in post-splicing steps of gene expression.
- Balbiani ring
-
Chromosome puffs or large diffused uncoiled regions, which are the sites of RNA transcription, in the giant polytene chromosomes of Chironomus tentans salivary gland cells.
- Exosome
-
A protein complex that has 3′ to 5′ exonuclease activity (although an endonuclease activity has also been described). Two forms of the exosome have been characterized that differ in their associated cofactors and cellular localization (one is nuclear and one is cytoplasmic).
- Promoter upstream non-coding transcripts
-
(PROMPTs). A recently discovered class of human RNAs. PROMPTs are produced upstream of promoters of active protein-coding genes. They are mainly nuclear and have poly(A) tails and 5′ cap structures.
- Nonsense-mediated mRNA decay
-
(NMD). The process by which mRNAs containing premature termination codons are destroyed to preclude the production of truncated and potentially deleterious protein products. It is also used in combination with specific alternative splicing events to control the levels of some proteins.
Rights and permissions
About this article
Cite this article
Müller-McNicoll, M., Neugebauer, K. How cells get the message: dynamic assembly and function of mRNA–protein complexes. Nat Rev Genet 14, 275–287 (2013). https://doi.org/10.1038/nrg3434
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg3434
This article is cited by
-
CRISPR-dCas13-tracing reveals transcriptional memory and limited mRNA export in developing zebrafish embryos
Genome Biology (2023)
-
RBP–RNA interactions in the control of autoimmunity and autoinflammation
Cell Research (2023)
-
Temporal-iCLIP captures co-transcriptional RNA-protein interactions
Nature Communications (2023)
-
The role of insulin-like growth factor 2 mRNA binding proteins in female reproductive pathophysiology
Reproductive Biology and Endocrinology (2022)
-
A comprehensive thermodynamic model for RNA binding by the Saccharomyces cerevisiae Pumilio protein PUF4
Nature Communications (2022)