Historically, the ribosome has been viewed as a constitutive molecular machine with little regulatory capacity in mRNA translation. However, recent findings suggest that ribosome composition and activity may be more dynamically regulated to impart a new layer of specificity in the control of gene expression.
Studies in several species have shown that 'specialized ribosomes' may exist, and that these ribosomes display heterogeneity in the composition and post-translational modifications of subsets of ribosomal proteins, variations in ribosomal RNA (rRNA) sequences or binding to distinct ribosome-associated factors. Greater variations in the translation machinery may have an substantial impact on how the genomic template is translated into functional proteins.
Specific cis-acting 'translational regulons' within mRNAs may interface with specialized ribosomes to confer translational specificity. Examples of these elements include internal ribosomal entry sites (IRESs) and upstream open reading frames (uORFs). Moreover, even core ribosome components that show little variation may exert a more specialized activity by virtue of their interactions with these specific regulatory elements.
Regulation in ribosome activity may provide an important new layer for control of gene expression in time and space that has an effect on cell and organismal biology as well as human disease.
It will be important to conceptualize mRNA translation in the same light as transcriptional control — as a process in which enhancers or attenuators are likely to fine-tune protein abundance and that culminates in unique readouts with important biological significance.
Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than intrinsic regulatory capacity in mRNA translation. However, emerging studies reveal that ribosome activity may be highly regulated. Heterogeneity in ribosome composition resulting from differential expression and post-translational modifications of ribosomal proteins, ribosomal RNA (rRNA) diversity and the activity of ribosome-associated factors may generate 'specialized ribosomes' that have a substantial impact on how the genomic template is translated into functional proteins. Moreover, constitutive components of the ribosome may also exert more specialized activities by virtue of their interactions with specific mRNA regulatory elements such as internal ribosome entry sites (IRESs) or upstream open reading frames (uORFs). Here we discuss the hypothesis that intrinsic regulation by the ribosome acts to selectively translate subsets of mRNAs harbouring unique cis-regulatory elements, thereby introducing an additional level of regulation in gene expression and the life of an organism.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Frank, J. The ribosome — a macromolecular machine par excellence. Chem. Biol. 7, R133–R141 (2000).
Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009). Reviews the mechanism of translation initiation and its regulation.
Alberts, B. The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell 92, 291–294 (1998).
Zaher, H. S. & Green, R. Fidelity at the molecular level: lessons from protein synthesis. Cell 136, 746–762 (2009).
Warner, J. R. The economics of ribosome biosynthesis in yeast. Trends Biochem. Sci. 24, 437–440 (1999).
Crick, F. H. C. The origin of the genetic code. J. Mol. Biol. 38, 367–379 (1968).
Nissen, P. The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920–930 (2000).
Noller, H. F., Hoang, L. & Fredrick, K. The 30S ribosomal P site: a function of 16S rRNA. FEBS Lett. 579, 855–858 (2005).
Noller, H. F., Hoffarth, V. & Zimniak, L. Unusual resistance of peptidyl extraction transferase to protein procedures. Science 256, 1416–1419 (1992).
Held, W. A., Mizushima, S. & Nomura, M. Reconstitution of Escherichia coli 30S ribosomal subunits from purified molecular components. J. Biol. Chem. 245, 5720–5730 (1973).
Rohl, R. & Nierhaus, K. H. Assembly map of the large subunit (50S) of Escherichia coli ribosomes. Proc. Natl Acad. Sci. USA 79, 729–733 (1982).
Balasubramanian, S. et al. Comparative analysis of processed ribosomal protein pseudogenes in four mammalian genomes. Genome Biol. 10, R2 (2009).
Kellis, M., Birren, B. W. & Lander, E. S. Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae. Nature 428, 617–624 (2004).
Ni, L. & Snyder, M. A genomic study of the bipolar bud site selection pattern in Saccharomyces cerevisiae. Mol. Biol. Cell 12, 2147–2170 (2001).
Enyenihi, A. H. & Saunders, W. S. Large-scale functional genomic analysis of sporulation and meiosis in Saccharomyces cerevisiae. Genetics 54, 47–54 (2003).
Ohtake, Y. & Wickner, R. B. Yeast virus propagation depends critically on free 60S ribsomal subunit concentration. Mol. Cell. Biol. 15, 2772–2781 (1995).
Carroll, K. & Wickner, R. B. Translation and M1 double-stranded RNA propagation: MAK18 = RPL41B and cycloheximide curing. J. Bacteriol. 177, 2887–2891 (1995).
Komili, S., Farny, N. G., Roth, F. P. & Silver, P. A. Functional specificity among ribosomal proteins regulates gene expression. Cell 131, 557–571 (2007).
Parenteau, J. et al. Introns within ribosomal protein genes regulate the production and function of yeast ribosomes. Cell 147, 320–331 (2011). Shows that introns in ribosomal protein genes regulate the expression of both the intron-containing genes and their paralogues.
Hughes, T. R. et al. Widespread aneuploidy revealed by DNA microarray expression profiling. Nature Genet. 25, 333–337 (2000).
Steffen, K. et al. Ribosome deficiency protects against ER stress in Saccharomyces cerevisiae. Genetics 191, 107–118 (2012).
Barakat, A. et al. The organization of cytoplasmic ribosomal protein genes in the arabidopsis genome. Plant Physiol. 127, 398–415 (2001).
Whittle, C. A. & Krochko, J. E. Transcript profiling provides evidence of functional divergence and expression networks among ribosomal protein gene paralogs in Brassica napus. Plant Cell 21, 2203–2219 (2009).
Weijers, D. et al. An. Arabidopsis Minute-like phenotype caused by a semi-dominant mutation in a ribosomal protein S5 gene. Development 128, 4289–4299 (2001). Shows differential expression of RPS5 paralogues in A. thaliana development.
Falcone Ferreyra, M. L., Pezza, A., Biarc, J., Burlingame, A. L. & Casati, P. Plant L10 ribosomal proteins have different roles during development and translation under ultraviolet-B stress. Plant Physiol. 153, 1878–1894 (2010).
Williams, M. E. & Sussex, I. M. Developmental regulation of ribosomal protein L16 genes in Arabidopsis thaliana. Plant J. 8, 65–76 (1995).
Degenhardt, R. F. & Bonham-Smith, P. C. Arabidopsis ribosomal proteins RPL23aA and RPL23aB are differentially targeted to the nucleolus and are disparately required for normal development. Plant Physiol. 147, 128–142 (2008).
Degenhardt, R. F. & Bonham-Smith, P. C. Transcript profiling demonstrates absence of dosage compensation in Arabidopsis following loss of a single RPL23a paralog. Planta 228, 627–640 (2008).
Marygold, S. J. et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol. 8, R216 (2007).
Kearse, M. G., Chen, A. S. & Ware, V. C. Expression of ribosomal protein L22e family members in Drosophila melanogaster: rpL22-like is differentially expressed and alternatively spliced. Nucleic Acids Res. 39, 2701–2716 (2011).
Lopes, A. M. et al. The human RPS4 paralogue on Yq11.223 encodes a structurally conserved ribosomal protein and is preferentially expressed during spermatogenesis. BMC Mol. Biol. 11, 33 (2010). Shows the differential expression of human RPS4 paralogues and predicts the differences in protein structures between the paralogues.
Fisher, E. M. et al. Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63, 1205–1218 (1990).
Sugihara, Y. et al. Proteomic analysis of rodent ribosomes revealed heterogeneity including ribosomal proteins L10-like, L22-like 1, and L39-like. J. Proteome Res. 9, 1351–1366 (2010).
Hariharan, N., Kelley, D. E. & Perry, R. P. Equipotent mouse ribosomal protein promoters have a similar architecture that includes internal sequence elements. Genes Dev. 3, 1789–1800 (1989).
Kim, C. H. & Warner, J. R. Messenger RNA for ribosomal proteins in yeast. J. Mol. Biol. 165, 79–89 (1983).
Bortoluzzi, S., D'Alessi, F., Romualdi, C. & Danieli, G. A. Differential expression of genes coding for ribosomal proteins in different human tissues. Bioinformatics 17, 1152–1157 (2001).
Kondrashov, N. et al. Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145, 383–397 (2011). First paper that shows heterogeneity in ribosomal protein expression in different tissues of a developing vertebrate embryo. It also shows that loss of a single ribosomal protein can have profound but specific effects on translational regulation in vivo.
Ramagopal, S. & Ennis, H. L. Regulation of synthesis of cell-specific ribosomal proteins during differentiation of Dictyostelium discoideum. Proc. Natl Acad. Sci. USA 78, 3083–3087 (1981).
Ramagopal, S. Induction of cell-specific ribosomal proteins in aggregation-competent nonmorphogenetic Dictyostelium discoideum. Biochem. Cell Biol. 68, 1281–1287 (1990). Demonstrates dramatic changes in ribosome composition as D. discoideum shifts from vegetatively growing to aggregation-competent.
Sahin, F. et al. RPL38, FOSL1, and UPP2 are predominantly expressed in the pancreatic ductal epithelium. Pancreas 30, 158–167 (2005).
Mills, A. A., Mills, M. J., Gardiner, D. M., Bryant, S. V. & Stanbridge, E. J. Analysis of the pattern of QM expression during mouse development. Differentiation 64, 161–171 (1999).
Green, H. et al. The ribosomal protein QM is expressed differentially during vertebrate endochondral bone development. J. Bone Miner. Res. 15, 1066–1075 (2000).
Subramanian, A. R. Copies of proteins L7 and L12 and heterogeneity of the large subunit of Escherichia coli ribosome. J. Mol. Biol. 95, 1–8 (1975).
Hardy, S. J. S. The stoichiometry of the ribosomal proteins of Escherichia coli. Mol. General Genet. 140, 253–274 (1975).
Oleinikov, A. V., Jokhadze, G. G. & Traut, R. R. A single-headed dimer of Escherichia coli ribosomal protein L7/L12 supports protein synthesis. Proc. Natl Acad. Sci. USA 95, 4215–4218 (1998).
Lam, Y. W., Lamond, A. I., Mann, M. & Andersen, J. S. Analysis of nucleolar protein dynamics reveals the nuclear degradation of ribosomal proteins. Curr. Biol. 17, 749–760 (2007).
Lee, S. W. et al. Direct mass spectrometric analysis of intact proteins of the yeast large ribosomal subunit using capillary LC/FTICR. Proc. Natl Acad. Sci. USA 99, 5942–5947 (2002).
Carroll, A. J. Heazlewood, J. L., Ito, J. & Millar, A. H. Analysis of the Arabidopsis cytosolic ribosome proteome provides detailed insights into its components and their post-translational modification. Mol. Cell. Proteomics. 7, 347–369 (2008).
Odintsova, T. I. et al. Characterization and analysis of posttranslational modifications of the human large cytoplasmic ribosomal subunit proteins by mass spectrometry and Edman sequencing. J. Protein Chem. 22, 249–258 (2003).
Yu, Y., Ji, H., Doudna, J. A. & Leary, J. A. Mass spectrometric analysis of the human 40S ribosomal subunit: native and HCV IRES-bound complexes. Protein Sci. 14, 1438–1446 (2005).
Ramagopal, S. Covalent modifications of ribosomal proteins in growing and aggregation-competent Dictyostelium discoideum: phosphorylation and methylation. Biochem. Cell Biol. 69, 263–268 (1991).
Krieg, J., Hofsteenge, J. & Thomas, G. Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide. J. Biol. Chem. 263, 11473–11477 (1988).
Ruvinsky, I. et al. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 19, 2199–2211 (2005).
Zeidan, Q., Wang, Z., De Maio, A. & Hart, G. W. O-GlcNAc cycling enzymes associate with the translational machinery and modify core ribosomal proteins. Mol. Biol. Cell 21, 1922–1936 (2010).
Spence, J. et al. Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain. Cell 102, 67–76 (2000).
Fleischer, T. C., Weaver, C. M., McAfee, K. J., Jennings, J. L. & Link, A. J. Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes Dev. 20, 1294–1307 (2006).
Colon-Ramos, D. A. et al. Direct ribosomal binding by a cellular inhibitor of translation. Nature Struct. Mol. Biol. 13, 103–111 (2006). Demonstrates that the translation regulator Reaper can bind directly to the 40S ribosome subunit to inhibit cap-dependent translational initiation.
Fuchs, G., Diges, C., Kohlstaedt, L. A., Wehner, K. A. & Sarnow, P. Proteomic analysis of ribosomes: translational control of mRNA populations by glycogen synthase GYS1. J. Mol. Biol. 410, 118–130 (2011).
Adams, D. R., Ron, D. & Kiely, P. A. RACK1, a multifaceted scaffolding protein: structure and function. Cell Commun. Signal. 9, 22 (2011).
Nilsson, J., Sengupta, J., Frank, J. & Nissen, P. Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome. EMBO Rep. 5, 1137–1141 (2004). Reviews, together with reference 59, the multiple functions of RACK1 as a protein that associates with the ribosome.
Ceci, M. et al. Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly. Nature 426, 574–579 (2003).
Jannot, G. et al. The ribosomal protein RACK1 is required for microRNA function in both C. elegans and humans. EMBO Rep. 12, 581–586 (2011).
Baum, S., Bittins, M., Frey, S. & Seedorf, M. Asc1p, a WD40-domain containing adaptor protein, is required for the interaction of the RNA-binding protein Scp160p with polysomes. Biochem. J. 380, 823–830 (2004).
Coyle, S. M., Gilbert, W. V. & Doudna, J. A. Direct link between RACK1 function and localization at the ribosome in vivo. Mol. Cell. Biol. 29, 1626–1634 (2009).
Li, A.-M., Watson, A. & Fridovich-Keil, J. L. Scp160p associates with specific mRNAs in yeast. Nucleic Acids Res. 31, 1830–1837 (2003).
Zoncu, R. Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).
Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011). Shows that mTORC2 interacts with the ribosome and this interaction activates mTORC2 independently of translation.
Oh, W. J. et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J. 29, 3939–3951 (2010).
Gunderson, J. et al. Structurally distinct, stage-specific ribosomes occur in Plasmodium. Science 238, 933–937 (1987). Shows that different forms of rRNAs are expressed in different stages in the lifecycle of Plasmodium berghei.
Velichutina, I. V., Rogers, M. J., McCutchan, T. F. & Liebman, S. W. Chimeric rRNAs containing the GTPase centers of the developmentally regulated ribosomal rRNAs of Plasmodium falciparum are functionally distinct. RNA 4, 594–602 (1998).
Rogers, M. J. et al. Structural features of the large subunit rRNA expressed in Plasmodium falciparum sprozoites that distinguish it from the asexually expressed large subunit rRNA. RNA 2, 134–145 (1996).
Pavlakis, G. N., Jordan, B. R., Wurst, R. M. & Vournakis, J. N. Sequence and secondary structure of Drosophila melanogaster 5.8 S and 2S rRNAs and of the processing site between them. Nucleic Acids Res. 7, 2213–2238 (1979).
Hassouna, N. Michot, B. & Bachellerie, J. P. The complete nucleotide sequence of mouse 28S rRNA gene. Implications for the process of size increase of the large subunit rRNA in higher eukaryotes. Nucleic Acids Res. 12, 3563–3583 (1984).
Ben-Shem, A. et al. The structure of the eukaryotic ribosome at 3.0 Å resolution. Science 334, 1524–1529 (2011).
Decatur, W. A. & Fournier, M. J. rRNA modifications and ribosome function. Trends Biochem. Sci. 27, 344–351 (2002).
Castle, J. C. et al. Digital genome-wide ncRNA expression, including SnoRNAs, across 11 human tissues using polyA-neutral amplification. PLoS ONE 5, e11779 (2010).
Hughes, M. E., Grant, G. R., Paquin, C., Qian, J. & Nitabach, M. N. Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res. 3 Apr 2012 (doi:10.1101/gr.128876.111).
Higa-Nakamine, S. et al. Loss of ribosomal RNA modification causes developmental defects in zebrafish. Nucleic Acids Res. 40, 391–398 (2012).
Mauro, V. P. & Edelman, G. M. The ribosome filter hypothesis. Proc. Natl Acad. Sci. USA 99, 12031–12036 (2002).
Spriggs, K. A., Stoneley, M., Bushell, M. & Willis, A. E. Re-programming of translation following cell stress allows IRES-mediated translation to predominate. Biol. Cell 100, 27–38 (2008).
Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320–325 (1988).
Jang, S. K. et al. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62, 2636–2643 (1988).
Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006). First paper that shows the importance of rRNA pseudouridylation in viral and cellular IRES-mediated translation.
Bellodi, C., Kopmar, N. & Ruggero, D. Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita. EMBO J. 29, 1865–1876 (2010).
Bellodi, C. et al. Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. Cancer Res. 70, 6026–6035 (2010).
Montanaro, L. et al. Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer Res. 70, 4767–4777 (2010).
Jack, K. et al. rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells. Mol. Cell 44, 660–666 (2011). Shows that rRNA pseudouridylation affects IRES-dependent translational initiation and translational fidelity.
Landry, D. M., Hertz, M. I. & Thompson, S. R. RPS25 is essential for translation initiation by the Dicistroviridae and hepatitis C viral IRESs. Genes Dev. 23, 2753–2764 (2009). Shows that a ribosomal protein interacts directly with an IRES element and regulates translation mediated by the IRES.
Muhs, M. et al. Structural basis for the binding of IRES RNAs to the head of the ribosomal 40S subunit. Nucleic Acids Res. 39, 5264–5275 (2011).
Horos, R. et al. Ribosomal deficiencies in Diamond–Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts. Blood 119, 262–272 (2012).
Calvo, S. E., Pagliarini, D. J. & Mootha, V. K. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc. Natl Acad. Sci. USA 106, 7507–7512 (2009).
Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).
Ingolia, N. T., Lareau, L. F. & Weissman, J. S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011).
Brar, G. A. et al. High-resolution view of the yeast meiotic program revealed by ribosome profiling. Science 335, 552–557 (2012).
Nishimura, T., Wada, T., Yamamoto, K. T. & Okada, K. The Arabidopsis STV1 protein, responsible for translation reinitiation, is required for auxin-mediated gynoecium patterning. Plant Cell 17, 2940–2953 (2005).
Park, H. S. et al. A plant viral “reinitiation” factor interacts with the host translational machinery. Cell 106, 723–733 (2001). Shows, together with reference 95, that RPL24 is important for the translational reinitiation of uORF containing mRNAs in plants.
Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Kozak, M. Initiation of translation in prokaryotes and eukaryotes. Gene 234, 187–208 (1999).
Vesper, O. et al. Selective translation of leaderless mRNAs by specialized ribosomes generated by MazF in Escherichia coli. Cell 147, 147–157 (2011). Shows that MazF in E.coli cleaves both rRNA and specific mRNAs, generating specialized ribosomes without the anti-Shine–Dalgarno sequence. These specialized ribosomes are competent to translate the leaderless mRNAs generated by MazF.
Byrne, M. E. A role for the ribosome in development. Trends Plant Sci. 14, 512–519 (2009). Reviews the myriad of ribosomal protein mutants in plants.
Szakonyi, D. & Byrne, M. E. Ribosomal protein L27a is required for growth and patterning in Arabidopsis thaliana. Plant J. 65, 269–281 (2011).
Pinon, V. et al. Three piggyback genes that specifically influence leaf patterning encode ribosomal proteins. Development 135, 1315–1324 (2008).
Brehme, K. S. Development of the Minute phenotype in Drosophila melanogaster. A comparative sudy of the growth of three Minute mutants. J. Exp. Zool. 88, 135–160 (1941).
Marygold, S. J., Coelho, C. M. & Leevers, S. J. Genetic analysis of RpL38 and RpL5, two Minute genes located in the centric heterochromatin of chromosome 2 of Drosophila melanogaster. Genetics 169, 683–695 (2005).
Kobayashi, S., Amikura, R. & Okada, M. Presence of mitochondrial large ribosomal RNA outside mitochondria in germ plasm of Drosophila melanogaster. Science 260, 1521–1524 (1993).
Amikura, R., Kashikawa, M., Nakamura, A. & Kobayashi, S. Presence of mitochondria-type ribosomes outside mitochondria in germ plasm of Drosophila embryos. Proc. Natl Acad. Sci. USA 98, 9133–9138 (2001).
Amikura, R., Sato, K. & Kobayashi, S. Role of mitochondrial ribosome-dependent translation in germline formation in Drosophila embryos. Mech. Dev. 122, 1087–1093 (2005).
Uechi, T. et al. Ribosomal protein gene knockdown causes developmental defects in zebrafish. PLoS ONE 1, e37 (2006).
Alexander, T., Nolte, C. & Krumlauf, R. Hox genes and segmentation of the hindbrain and axial skeleton. Annu. Rev. Cell Dev. Biol. 25, 431–456 (2009).
Wellik, D. M. Hox patterning of the vertebrate axial skeleton. Dev. Dyn. 236, 2454–2463 (2007).
Oliver, E. R., Saunders, T. L., Tarle, S. A. & Glaser, T. Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131, 3907–3920 (2004).
Oristian, D. S. et al. Ribosomal protein L29/HIP deficiency delays osteogenesis and increases fragility of adult bone in mice. J. Orthop. Res. 27, 28–35 (2009).
Zhang, Y. & Lu, H. Signaling to p53: ribosomal proteins find their way. Cancer Cell 16, 369–377 (2009).
Chakraborty, A., Uechi, T., Higa, S., Torihara, H. & Kenmochi, N. Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response. PLoS ONE 4, e4152 (2009).
Duan, J. et al. Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish. Int. J. Biochem. Cell Biol. 43, 1218–1227 (2011).
Danilova, N., Sakamoto, K. M. & Lin, S. Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112, 5228–5237 (2008).
Panic, L. et al. Ribosomal protein S6 gene haploinsufficiency is associated with activation of a p53-dependent checkpoint during gastrulation. Mol. Cell. Biol. 26, 8880–8891 (2006).
Boria, I. et al. The ribosomal basis of Diamond–Blackfan anemia: mutation and database update. Hum. Mutat. 31, 1269–1279 (2010).
Gazda, H. T. et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond–Blackfan anemia patients. Am. J. Hum. Genet. 83, 769–780 (2008).
Zhou, C. et al. Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex. Hum. Mutat. 32, 710–714 (2011).
Bramham, C. R. & Wells, D. G. Dendritic mRNA: transport, translation and function. Nature Rev. Neurosci. 8, 776–789 (2007).
Vickers, C. A., Dickson, K. S. & Wyllie, D. J. Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones. J. Physiol. 568, 803–813 (2005).
Ostroff, L. E., Fiala, J. C., Allwardt, B. & Harris, K. M. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35, 535–545 (2002).
Moroz, L. L. et al. Neuronal transcriptome of Aplysia: neuronal compartments and circuitry. Cell 127, 1453–1467 (2006). Characterizes the mRNAs found in neuronal processes and finds an enrichment of ribosomal protein mRNAs in processes as compared to the soma.
Sossin, W. S. & DesGroseillers, L. Intracellular trafficking of RNA in neurons. Traffic 7, 1581–1589 (2006).
Moccia, R. et al. An unbiased cDNA library prepared from isolated Aplysia sensory neuron processes is enriched for cytoskeletal and translational mRNAs. J. Neurosci. 23, 9409–9417 (2003).
Tcherkezian, J., Brittis, P. A., Thomas, F., Roux, P. P. & Flanagan, J. G. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141, 632–644 (2010).
Pinkstaff, J. K., Chappell, S. A., Mauro, V. P., Edelman, G. M. & Krushel, L. A. Internal initiation of translation of five dendritically localized neuronal mRNAs. Proc. Natl Acad. Sci. USA 98, 2770–2775 (2001).
Kressler, D., Hurt, E. & Bassler, J. Driving ribosome assembly. Biochim. Biophys. Acta 1803, 673–683 (2010).
Baxter-Roshek, J. L., Petrov, A. N. & Dinman, J. D. Optimization of ribosome structure and function by rRNA base modification. PLoS ONE 2, e174 (2007).
Schafer, T. et al. Hrr25-dependent phosphorylation state regulates organization of the pre-40S subunit. Nature 441, 651–655 (2006).
Martin-Marcos, P., Hinnebusch, A. G. & Tamame, M. Ribosomal protein L33 is required for ribosome biogenesis, subunit joining, and repression of GCN4 translation. Mol. Cell. Biol. 27, 5968–5985 (2007).
Ferreira-Cerca, S. et al. Analysis of the in vivo assembly pathway of eukaryotic 40S ribosomal proteins. Mol. Cell 28, 446–457 (2007).
Peltz, S. W. et al. Ribosomal protein L3 mutants alter translational fidelity and promote rapid loss of the yeast killer virus. Mol. Cell. Biol. 19, 384–391 (1999).
Rhodin, M. H., Rakauskaite, R. & Dinman, J. D. The central core region of yeast ribosomal protein L11 is important for subunit joining and translational fidelity. Mol. Genet. Genomics 285, 505–516 (2011).
Henras, A. K. et al. The post-transcriptional steps of eukaryotic ribosome biogenesis. Cell. Mol. Life Sci. 65, 2334–2359 (2008).
Johnson, A. W., Lund, E. & Dahlberg, J. Nuclear export of ribosomal subunits. Trends Biochem. Sci. 27, 580–585 (2002).
Warner, J. R. & McIntosh, K. B. How common are extraribosomal functions of ribosomal proteins? Mol. Cell 34, 3–11 (2009). Examines the extraribosomal function of many ribosomal proteins.
Dabeva, M. D. & Warner, J. R. Ribosomal protein L32 of Saccharomyces cerevisiae regulates both splicing and translation of its own transcript. J. Biol. Chem. 268, 19669–19674 (1993).
Malygin, A. A., Parakhnevitch, N. M., Ivanov, A. V., Eperon, I. C. & Karpova, G. G. Human ribosomal protein S13 regulates expression of its own gene at the splicing step by a feedback mechanism. Nucleic Acids Res. 35, 6414–6423 (2007).
Wan, F. et al. Ribosomal protein S3: a KH domain subunit in NF-κB complexes that mediates selective gene regulation. Cell 131, 927–939 (2007).
Mazumder, B. & Fox, P. L. Delayed translational silencing of ceruloplasmin transcript in γ-interferon-activated U937 monocytic cells: role of the 3′ untranslated region. Mol. Cell. Biol. 19, 6898–6905 (1999).
Mazumder, B. et al. Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell 115, 187–198 (2003).
Kapasi, P. et al. L13a blocks 48S assembly: role of a general initiation factor in mRNA-specific translational control. Mol. Cell 25, 113–126 (2007).
Vyas, K. et al. Genome-wide polysome profiling reveals an inflammation-responsive posttranscriptional operon in γ-interferon-activated monocytes. Mol. Cell. Biol. 29, 458–470 (2009).
Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).
The authors would like to thank D. Ruggero, C. Bellodi, M. McMahon, C. Stumpf and members of the Barna laboratory for discussion and critical reading of the manuscript. S.X. is supported by the Agency of Science, Technology and Research of Singapore. This work was supported by the Program for Breakthrough Biomedical Research, UCSF (to M.B.) and the National Institutes of Health (NIH) Director's New Innovator Award, 1DP2OD008509 (to M.B.).
The authors declare no competing financial interests.
A conserved organelle that assembles around ribosomal DNA genes. The nucleolus is the site of ribosomal RNA transcription and the site of ribosome subunit assembly.
Homologous genes that are separated by a duplication event and that have evolved new functions.
(Asymmetric synthesis of homothallic switching endonuclease (HO)). A gene encoding a repressor that inhibits the transcription of HO — an endonuclease that causes mating-type switching in Saccharomyces cerevisiae. ASH1 mRNA is transported to the bud before translation. In the bud, Ash1 prevents the daughter cell from switching its mating type following cell division.
Or polyribosomes; clusters of two or more ribosomes attached at different sites on the same strand of mRNA. mRNAs bound to polysomes are being actively translated.
Blocks of mesoderm on either side of the neural tube of a developing vertebrate embryo. Somites will develop into structures including the vertebrae.
- Mammalian target of rapamycin complex 2
(mTORC2). A protein kinase complex that includes mTOR, RICTOR and other proteins. mTORC2 regulates cell growth, metabolism and survival in response to environmental cues such as nutrients and growth factors.
The cellular form of Plasmodium parasites when they infect a new host.
- Expansion segments
A region of ribosomal RNA (rRNA) that has dramatically increased in length from prokaryotes to eukaryotes during evolution.
- Small nucleolar RNAs
(snoRNAs). Small RNA molecules that function in ribosome biogenesis in the nucleolus by guiding the assembly of macromolecular complexes on the target RNA to allow site-specific modifications or processing reactions to occur.
- Upstream open reading frame
(uORF). An uORF is defined by a start codon and an in-frame stop codon in the 5′ untranslated region of an mRNA.
- Shine–Dalgarno sequence
A ribosomal binding site of approximately eight nucleotides in the mRNA of bacteria, located upstream of the initiation codon. Helps to recruit the small ribosomal subunit to the mRNA to initiate protein synthesis.
- Cleft palate
A craniofacial abnormality that results from a failure to fuse the left and right palatal shelves at the midline during embryogenesis. It can be caused by several environmental and genetic factors, including defects in sonic hedgehog signalling.
- Long-term potentiation
(LTP). A long-lasting increase in the size of the postsynaptic response to synaptic transmissions. LTP is thought to be a key mechanism for learning and long-term memory formation in the brain.
About this article
Cite this article
Xue, S., Barna, M. Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nat Rev Mol Cell Biol 13, 355–369 (2012). https://doi.org/10.1038/nrm3359
Biology Open (2020)
Genome Biology (2020)
Differential expression of duplicated ribosomal protein genes modifies ribosome composition in response to stress
Nucleic Acids Research (2020)
Scientific Reports (2020)
Genome-wide translational reprogramming of genes important for myocyte functions in overload-induced heart failure
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2020)