Following transcription, genomic information begins a long journey toward translation of its nucleotide sequence into the amino acids of a protein. In eukaryotes, synthesized pre-mRNAs become processed to mature mRNAs by 5′-end capping, splicing, 3′-end cleavage and polyadenylation in the nucleus, before being scrutinized for premature stop codons. Each step requires high precision and control to ensure that an intact and readable message is exported to the cytoplasm before finally becoming translated. Two important aspects of these processes are accurately managed by ribonucleoprotein machineries—the spliceosome and the ribosome. Recently, several natural products targeting these macromolecular assemblies have been reported. For the first time in eukaryotes, these molecules allow chemical disruption and dissection of the sophisticated machinery that regulates post-transcriptional events. Beyond their great potential as bioprobes for investigating mRNA regulation and protein synthesis, these compounds also show promise in opening new therapeutic approaches.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Splicing controls the ubiquitin response during DNA double-strand break repair
Cell Death & Differentiation Open Access 17 June 2016
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Staley, J.P. & Woolford, J.L. Jr. Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines. Curr. Opin. Cell Biol. 21, 109–118 (2009).
Wahl, M.C., Will, C.L. & Lührmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).
Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J. Antibiot. (Tokyo) 49, 1196–1203 (1996).
Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J. Antibiot. (Tokyo) 49, 1204–1211 (1996).
Nakajima, H., Kim, Y.B., Terano, H., Yoshida, M. & Horinouchi, S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp. Cell Res. 241, 126–133 (1998).
Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3, 576–583 (2007).
Horigome, M., Motoyoshi, H., Watanabe, H. & Kitahara, T. A synthesis of FR901464. Tetrahedr. Lett. 42, 8207–8210 (2001).
Thompson, C.F., Jamison, T.F. & Jacobsen, E.N. FR901464: total synthesis, proof of structure, and evaluation of synthetic analogues. J. Am. Chem. Soc. 123, 9974–9983 (2001).
Albert, B.J., Sivaramakrishnan, A., Naka, T., Czaicki, N.L. & Koide, K. Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue. J. Am. Chem. Soc. 129, 2648–2659 (2007).
Albert, B.J. et al. Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells. Mol. Cancer Ther. 8, 2308–2318 (2009).
Sakai, T. et al. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. J. Antibiot. (Tokyo) 57, 173–179 (2004).
Sakai, T., Asai, N., Okuda, A., Kawamura, N. & Mizui, Y. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. II. Physico-chemical properties and structure elucidation. J. Antibiot. (Tokyo) 57, 180–187 (2004).
Kotake, Y. et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat. Chem. Biol. 3, 570–575 (2007).
O'Brien, K., Matlin, A.J., Lowell, A.M. & Moore, M.J. The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing. J. Biol. Chem. 283, 33147–33154 (2008).
Soret, J. et al. Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors. Proc. Natl. Acad. Sci. USA 102, 8764–8769 (2005).
Stoilov, P., Lin, C.H., Damoiseaux, R., Nikolic, J. & Black, D.L. A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators. Proc. Natl. Acad. Sci. USA 105, 11218–11223 (2008).
Hagiwara, M. Alternative splicing: a new drug target of the post-genome era. Biochim. Biophys. Acta 1754, 324–331 (2005).
Martinez, E. et al. Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Mol. Cell. Biol. 21, 6782–6795 (2001).
Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).
Kuhn, A.N., van Santen, M.A., Schwienhorst, A., Urlaub, H. & Luhrmann, R. Stalling of spliceosome assembly at distinct stages by small-molecule inhibitors of protein acetylation and deacetylation. RNA 15, 153–175 (2009).
Balasubramanyam, K., Swaminathan, V., Ranganathan, A. & Kundu, T.K. Small molecule modulators of histone acetyltransferase p300. J. Biol. Chem. 278, 19134–19140 (2003).
Balasubramanyam, K. et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J. Biol. Chem. 279, 33716–33726 (2004).
Ban, N., Nissen, P., Hansen, J., Moore, P.B. & Steitz, T.A. The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. Science 289, 905–920 (2000).
Brodersen, D.E. et al. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103, 1143–1154 (2000).
Wimberly, B.T. et al. Structure of the 30S ribosomal subunit. Nature 407, 327–339 (2000).
Tu, D., Blaha, G., Moore, P.B. & Steitz, T.A. Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121, 257–270 (2005).
Schroeder, S.J., Blaha, G., Tirado-Rives, J., Steitz, T.A. & Moore, P.B. The structures of antibiotics bound to the E site region of the 50 S ribosomal subunit of Haloarcula marismortui: 13-deoxytedanolide and girodazole. J. Mol. Biol. 367, 1471–1479 (2007).
Lecompte, O., Ripp, R., Thierry, J.C., Moras, D. & Poch, O. Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. Nucleic Acids Res. 30, 5382–5390 (2002).
Hermann, T. Drugs targeting the ribosome. Curr. Opin. Struct. Biol. 15, 355–366 (2005).
Sutcliffe, J.A. Improving on nature: antibiotics that target the ribosome. Curr. Opin. Microbiol. 8, 534–542 (2005).
Schroeder, R., Waldsich, C. & Wank, H. Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 19, 1–9 (2000).
Chopra, I. & Roberts, M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol. Mol. Biol. Rev. 65, 232–260 (2001).
Nierhaus, D. & Nierhaus, K.H. Identification of the chloramphenicol-binding protein in Escherichia coli ribosomes by partial reconstitution. Proc. Natl. Acad. Sci. USA 70, 2224–2228 (1973).
Bashan, A. et al. Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. Mol. Cell 11, 91–102 (2003).
Tenson, T., Lovmar, M. & Ehrenberg, M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J. Mol. Biol. 330, 1005–1014 (2003).
Hurdle, J.G., O' Neill, A.J. & Chopra, I. Prospects for aminoacyl-tRNA synthetase inhibitors as new antimicrobial agents. Antimicrob. Agents Chemother. 49, 4821–4833 (2005).
Rodnina, M.V. et al. Thiostrepton inhibits the turnover but not the GTPase of elongation factor G on the ribosome. Proc. Natl. Acad. Sci. USA 96, 9586–9590 (1999).
Heffron, S.E. & Jurnak, F. Structure of an EF-Tu complex with a thiazolyl peptide antibiotic determined at 2.35 A resolution: atomic basis for GE2270A inhibition of EF-Tu. Biochemistry 39, 37–45 (2000).
Eustice, D.C. & Wilhelm, J.M. Mechanisms of action of aminoglycoside antibiotics in eucaryotic protein synthesis. Antimicrob. Agents Chemother. 26, 53–60 (1984).
Nathans, D. Puromycin inhibition of protein synthesis: incorporation of puromycin into peptide chains. Proc. Natl. Acad. Sci. USA 51, 585–592 (1964).
Justice, M.C. et al. Elongation factor 2 as a novel target for selective inhibition of fungal protein synthesis. J. Biol. Chem. 273, 3148–3151 (1998).
Ahuja, D. et al. Inhibition of protein synthesis by didemnin B: how EF-1alpha mediates inhibition of translocation. Biochemistry 39, 4339–4346 (2000).
Gomez-Lorenzo, M.G. et al. Three-dimensional cryo-electron microscopy localization of EF2 in the Saccharomyces cerevisiae 80S ribosome at 17.5 A resolution. EMBO J. 19, 2710–2718 (2000).
Jorgensen, R. et al. Two crystal structures demonstrate large conformational changes in the eukaryotic ribosomal translocase. Nat. Struct. Biol. 10, 379–385 (2003).
Vazquez, D. Inhibitors of protein biosynthesis. Mol. Biol. Biochem. Biophys. 30, i–x, 1–312 (1979).
Takahashi, H. et al. Reveromycins, new inhibitors of eukaryotic cell growth. II. Biological activities. J. Antibiot. (Tokyo) 45, 1414–1419 (1992).
Miyamoto, Y. et al. Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as a target of the G1-specific inhibitor Reveromycin A. J. Biol. Chem. 277, 28810–28814 (2002).
Hood, K.A., West, L.M., Northcote, P.T., Berridge, M.V. & Miller, J.H. Induction of apoptosis by the marine sponge (Mycale) metabolites, mycalamide A and pateamine. Apoptosis 6, 207–219 (2001).
Sugawara, K. et al. Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity. J. Antibiot. (Tokyo) 45, 1433–1441 (1992).
Lee, K.H. et al. Inhibition of protein synthesis and activation of stress-activated protein kinases by onnamide A and theopederin B, antitumor marine natural products. Cancer Sci. 96, 357–364 (2005).
Chan, J., Khan, S.N., Harvey, I., Merrick, W. & Pelletier, J. Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles. RNA 10, 528–543 (2004).
Kapp, L.D. & Lorsch, J.R. The molecular mechanics of eukaryotic translation. Annu. Rev. Biochem. 73, 657–704 (2004).
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).
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).
Northcote, P.T., Blunt, J.W. & Munro, M.H.G. Pateamine: a potent cytotoxin from the New Zealand marine sponge Mycale sp. Tetrahedr. Lett. 32, 6411–6414 (1991).
Rzasa, R.M., Shea, H.A. & Romo, D. Total synthesis of the novel, immunosuppressive agent (-)-pateamine A from Mycale sp. employing a β-lactam-based macrocyclization. J. Am. Chem. Soc. 120, 591–592 (1998).
Low, W.K. et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell 20, 709–722 (2005).
Bordeleau, M.E. et al. Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation. Proc. Natl. Acad. Sci. USA 102, 10460–10465 (2005).
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).
Dang, Y. et al. Eukaryotic initiation factor 2α-independent pathway of stress granule induction by the natural product pateamine A. J. Biol. Chem. 281, 32870–32878 (2006).
Mazroui, R. et al. Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2α phosphorylation. Mol. Biol. Cell 17, 4212–4219 (2006).
Kedersha, N. & Anderson, P. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem. Soc. Trans. 30, 963–969 (2002).
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).
Kuznetsov, G. et al. Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A. Mol. Cancer Ther. 8, 1250–1260 (2009).
Bordeleau, M.E. et al. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat. Chem. Biol. 2, 213–220 (2006).
Lindqvist, L. et al. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS One 3, e1583 (2008).
Obrig, T.G., Culp, W.J., McKeehan, W.L. & Hardesty, B. The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J. Biol. Chem. 246, 174–181 (1971).
Pestova, T.V. & Hellen, C.U. Translation elongation after assembly of ribosomes on the Cricket paralysis virus internal ribosomal entry site without initiation factors or initiator tRNA. Genes Dev. 17, 181–186 (2003).
Schneider-Poetsch, T. et al. Inhibition of translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6, 209–217 (2010).
Nakae, K. et al. Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929–43F1. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. (Tokyo) 53, 1130–1136 (2000).
Woo, E.J. et al. Migrastatin and a new compound, isomigrastatin, from Streptomyces platensis. J. Antibiot. (Tokyo) 55, 141–146 (2002).
Takemoto, Y., Tashiro, E. & Imoto, M. Suppression of multidrug resistance by migrastatin. J. Antibiot. (Tokyo) 59, 435–438 (2006).
Shan, D. et al. Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. Proc. Natl. Acad. Sci. USA 102, 3772–3776 (2005).
Ju, J., Lim, S.K., Jiang, H. & Shen, B. Migrastatin and dorrigocins are shunt metabolites of iso-migrastatin. J. Am. Chem. Soc. 127, 1622–1623 (2005).
Ju, J. et al. Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration. J. Am. Chem. Soc. 131, 1370–1371 (2009).
Gurel, G., Blaha, G., Steitz, T.A. & Moore, P.B. The structures of triacetyloleandomycin and mycalamide A bound to the large ribosomal subunit of Haloarcula marismortui. Antimicrob. Agents Chemother. 53, 5010–5014 (2009).
Nishimura, S. et al. 13-Deoxytedanolide, a marine sponge-derived antitumor macrolide, binds to the 60S large ribosomal subunit. Bioorg. Med. Chem. 13, 449–454 (2005).
Fresno, M., Jimenez, A. & Vazquez, D. Inhibition of translation in eukaryotic systems by harringtonine. Eur. J. Biochem. 72, 323–330 (1977).
Gurel, G., Blaha, G., Moore, P.B. & Steitz, T.A. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J. Mol. Biol. 389, 146–156 (2009).
Quintas-Cardama, A., Kantarjian, H. & Cortes, J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer 115, 5382–5393 (2009).
Kucuk, O. et al. Phase II trail of didemnin B in previously treated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group (ECOG) study. Am. J. Clin. Oncol. 23, 273–277 (2000).
Le Tourneau, C. et al. Reports of clinical benefit of plitidepsin (Aplidine), a new marine-derived anticancer agent, in patients with advanced medullary thyroid carcinoma. Am. J. Clin. Oncol. (2009).
Ocio, E.M., Mateos, M.V., Maiso, P., Pandiella, A. & San-Miguel, J.F. New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol. 9, 1157–1165 (2008).
Robert, F. et al. Altering chemosensitivity by modulating translation elongation. PLoS One 4, e5428 (2009).
Beretta, L., Gingras, A.C., Svitkin, Y.V., Hall, M.N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E–BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15, 658–664 (1996).
Averous, J. & Proud, C.G. When translation meets transformation: the mTOR story. Oncogene 25, 6423–6435 (2006).
Woo, J.T. et al. Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. Proc. Natl. Acad. Sci. USA 103, 4729–4734 (2006).
Hiraoka, K. et al. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 99, 1595–1602 (2008).
Faustino, N.A. & Cooper, T.A. Pre-mRNA splicing and human disease. Genes Dev. 17, 419–437 (2003).
Ng, B. et al. Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes. J. Allergy Clin. Immunol. 114, 1463–1470 (2004).
Wang, G.S. & Cooper, T.A. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat. Rev. Genet. 8, 749–761 (2007).
Blencowe, B.J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006).
Kim, Y.K. & Kim, V.N. Processing of intronic microRNAs. EMBO J. 26, 775–783 (2007).
Bayne, E.H. et al. Splicing factors facilitate RNAi-directed silencing in fission yeast. Science 322, 602–606 (2008).
Hirose, T., Shu, M.D. & Steitz, J.A. Splicing-dependent and -independent modes of assembly for intron-encoded box C/D snoRNPs in mammalian cells. Mol. Cell 12, 113–123 (2003).
Kataoka, N., Fujita, M. & Ohno, M. Functional association of the Microprocessor complex with the spliceosome. Mol. Cell. Biol. 29, 3243–3254 (2009).
Lee, K.H. et al. Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. Biosci. Biotechnol. Biochem. 70, 161–171 (2006).
We thank J.O. Liu of the Johns Hopkins University School of Medicine for his support and for making an unpublished manuscript available to us.
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Schneider-Poetsch, T., Usui, T., Kaida, D. et al. Garbled messages and corrupted translations. Nat Chem Biol 6, 189–198 (2010). https://doi.org/10.1038/nchembio.326
This article is cited by
Splicing controls the ubiquitin response during DNA double-strand break repair
Cell Death & Differentiation (2016)
Erratum: Garbled messages and corrupted translations
Nature Chemical Biology (2010)