The nucleolus is a large nuclear domain generated by the act of building ribosomes. It illustrates the compartmentation of the nuclear functions, since it is in the nucleolus that transcription of the ribosomal genes, maturation and processing of the 47S ribosomal RNAs (rRNAs) into 18S, 5.8S and 28S rRNA, and almost complete assembly of the 40S and 60S ribosome subunits take place. The shape, size and organization of the nucleoli vary with their activity. Nuleolar activity is a cell cycle dependent-process. In electron microscopy, the nucleolus exhibits three main components: fibrillar centers (FCs), a dense fibrillar component (DFC) and a granular component (GC), corresponding to different steps of ribosome biogenesis. The steady state between transcription, processing and export of ribosomal subunits engenders this organization. Conversely, inactivation or blockage of one of these processes modifies the organization of the nucleolus and ultimately induces nucleolar disassembly. The nucleolus is also a plurifunctional domain, a key partner of chromatin architecture in the nucleus and it plays a crucial role in several cellular functions in addition to ribosome production.
The nucleolus is assembled at the end of mitosis, is active during interphase, and disassembled in prophase. The nucleolar transcription and processing machineries are inherited from parental to daughter cells through mitosis. The polymerase I (pol I) transcription machinery is repressed during mitosis although assembled with ribosomal genes. Repression of pol I transcription is achieved at the end of prophase and is maintained during mitosis through phosphorylation of transcription factors by the cyclin-dependent kinase (CDK) 1. The nucleolar processing machineries relocalize from the nucleolus towards the periphery of all chromosomes until telophase and this chromosome association depends on CDK1 activity. As a consequence of natural inhibition of CDK1 activity, pol I transcription is restored in telophase. The processing machineries are recruited to the sites of rDNA transcription after a temporary transit in foci known as prenucleolar bodies.
In conclusion, the behavior of the nucleolus illustrates the fact that the dynamics of nuclear organization are integrated in a network of interactions and controls that is largely dependent on the coordination of cell cycle controls.
nucleolus; cell cycle; dynamics; organization; nuclear domain; ribosome
Andersen J, Lyon CE, Fox AH, Leung AKL, Lam YW, Steen H, Mann M, Lamond AI: Directed proteomic analysis of the human nucleolus. Curr Biol 12:1-11, 2002.
Bell P, Dabauvalle MC, Scheer U: In vitro assembly of prenucleolar bodies in Xenopus egg extract. J Cell Biol 118:1297-1304, 1992.
Beven AF, Lee R, Razaz M, Leader DJ, Brown JWS, Shaw PJ: The organization of ribosomal RNA processing correlates with the distribution of nucleolar snRNAs. J Cell Sci 109:1241-1251, 1996.
Biggiogera M, Malatesta M, Abolhassani-Dadras S, Amalric F, Rothblum LI, Fakan S: Revealing the unseen: the organizer of the nucleolus. J Cell Sci 17:3199-3205, 2001.
Busch H, Smetana K: The nucleus of cancer cells. In Busch H (ed), The Molecular Biology of Cancer. Academic Press, New York 1974, pp. 41-80.
Carmo-Fonseca M, Mendes-Soares L, Campos I: To be or not to be in the nucleolus. Nature Cell Biol 2:107-112, 2000.
Chubb JR, Boyle S, Perry P, Bickmore WA: Chromatin motion is constrained by association with nuclear compartments in human cells. Curr Biol 12:439-445, 2002.
Cmarko D, Verschure PJ, Rothblum LI, Hernandez-Verdun D, Amalric F, van Driel R, Fakan S: Ultrastructural analysis of nucleolar transcription in cells microinjected with 5-bromo-UTP. Histochem Cell Biol 113:181-187, 2000.
Dousset T, Wang C, Verheggen C, Chen D, Hernandez-Verdun D, Huang S: Initiation of nucleolar assembly is independent of RNA polymerase I transcription. Mol Biol Cell 11:2705-2717, 2000.
Dundr M, Misteli T, Olson MOJ: The dynamics of postmitotic reassembly of the nucleolus. J Cell Biol 150:433-446, 2000.
Dundr M, Olson MOJ: Partially processed pre-rRNA is preserved in association with processing components in nucleolus derived foci during mitosis. Mol Biol Cell 9:2407-2422, 1998.
Fan H, Penman S: Regulation of synthesis and processing of nucleolar components in metaphase-arrested cells. J Mol Biol 59:27-42, 1971.
Fatica A, Tollervey D: Making ribosomes. Curr Opin Cell Biol 14:313-318, 2002.
Fomproix N, Gebrane-Younes J, Hernandez-Verdun D: Effects of anti-fibrillarin antibodies on building of functional nucleoli at the end of mitosis. J Cell Sci 111:359-372, 1998.
Gautier T, Fomproix N, Masson C, Azum-Gelade MC, Gas N, Hernandez-Verdun D: Fate of specific nucleolar perichromosomal proteins during mitosis: Cellular distribution and association with U3 snoRNA. Biol Cell 82:81-93, 1994.
Gebrane-Younes J, Fomproix N, Hernandez-Verdun D: When rDNA transcription is arrested during mitosis, UBF is still associated with non-condensed rDNA. J Cell Sci 110:2429-2440, 1997.
Gerlich D, Beaudouin J, Kalbfuss B, Daigle N, Eils R, Ellenberg J: Global chromosome positions are transmitted through mitosis in mammalian cells. Cell 112:751, 2003.
Goessens G: Nucleolar structure. Int Rev Cytol 87:107-158, 1984.
Granick D: Nucleolar necklaces in chick embryo fibroblast cells. I. Formation of necklaces by dichlororibobenzimidazole and other adenosine analogues that decrease RNA synthesis and degrade preribosomes. J Cell Biol 65:398-417, 1975a.
Granick D: Nucleolar necklaces in chick embryo fibroblast cells. II. Microscope observations of the effect of adenosine analogues on nucleolar necklace formation. J Cell Biol 65:418-427, 1975b.
Haaf T, Ward DC: Inhibition of RNA polymerase II transcription causes chromatin decondensation, loss of nucleolar structure, and dispersion of chromosomal domains. Exp Cell Res 224:163-173, 1996.
Hadjiolov AA: The nucleolus and ribosome biogenesis. In Alfert M, Beermann W, Goldstein L, Porter KR, Sitte P, (eds): Cell Biology Monographs, Vol. 12, Springer-Verlag, Wien 1985.
Harnpicharnchai P, Jakovljevic J, Horsey E, Miles T, Roman J, Rout M, Meagher D, Imai B, Guo Y, Brame CJ, Shabanowitz J, Hunt DF, Woolford JL: Composition and functional characterization of yeast 66S ribosome assembly intermediates. Mol Cell 8:505-515, 2001.
Heix J, Vente A, Voit R, Budde A, Michaelidis TM, Grummt I: Mitotic silencing of human rRNA synthesis: inactivation of the promoter selectivity factor SL1 by cdc2/cyclin B-mediated phosphorylation. EMBO J 17:7373-7381, 1998.
Hernandez-Verdun D, Bourgeois CA, Bouteille M: Simultaneous nucleologenesis in daughter cells during late telophase. Bio Cell 37:1-4, 1980.
Hozak P, Novak JT, Smetana K: Three-dimensional reconstructions of nucleolus-organizing regions in PHA-stimulated human lymphocytes. Biol Cell 66:225-233, 1989.
Jimenez-Garcia LF, de L Segura-Valdez M, Ochs RL, Rothblum LI, Hannan R, Spector DL: Nucleologenesis: U3 snRNA-containing prenucleolar bodies move to sites of active pre-rRNA transcription after mitosis. Mol Biol Cell 5:955-966, 1994.
Junera HR, Masson C, Geraud G, Hernandez-Verdun D: The three-dimensional organization of ribosomal genes and the architecture of the nucleoli vary with G1, S and G2 phases. J Cell Sci 108:3427-3441, 1995.
Junera HR, Masson C, Geraud G, Suja J, Hernandez-Verdun D: Involvement of in situ conformation of ribosomal genes and selective distribution of UBF in rRNA transcription. Mol Biol Cell 8:145-156, 1997.
Le Panse S, Masson C, Heliot L, Chassery J-M, Junera HR, Hernandez-Verdun D: 3-D organization of single ribosomal transcription units after DRB inhibition of RNA polymerase II transcription. J Cell Sci 112:2145-2154, 1999.
Leung AKL, Lamond AI: In vivo analysis of NHPX reveals a novel nucleolar localization pathway involving a transient accumulation in splicing speckles. J Cell Biol 157:615-629, 2002.
McClintock B: The relation of particular chromosomal element to the development of the nucleoli in Zea mays. Z Zellforsch mikrosk Anat 21:294-328, 1934.
Melese T, Xue Z: The nucleolus: an organelle formed by the act of buiding a ribosome. Cur Opin Cell Biol 7:319-324, 1995.
Misteli T: Protein dynamics: implications for nuclear architecture and gene expression. Science 291:843-847, 2001.
Moyne G, Garrido J: Ultrastructural evidence of mitotic perichromosomal ribonucleoproteins in hamster cells. Exp Cell Res 98:237-247, 1976.
Nissan TA, Bassler J, Petfalski E, Tollervey D, Hurt E: 60S pre-ribosome formation viewed from assembly in the nucleolus until export to the cytoplasm. EMBO J 21:5539-5547, 2002.
Olson MOJ, Dundr M, Szebeni A: The nucleolus: an old factory with unexpected capabilities. Trends Cell Biol 10:189-196, 2000.
Pebusque MJ, Seite R: Electron microscopic studies of silver-stained proteins in nucleolar organizer regions: location in nucleoli of rat sympathetic neurons during light and dark periods. J Cell Sci 51:85-94, 1981.
Pederson T: The plurifunctional nucleolus. Nucl Acids Res 26:3871-3876, 1998.
Phair RD, Misteli T: High mobility of proteins in the mammalian cell nucleus. Nature 404:604-609, 2000.
Pinol-Roma S: Association of nonribosomal nucleolar proteins in ribonucleoprotein complexes during interphase and mitosis. Mol Biol Cell 10:77-90, 1999.
Prescott DM, Bender MA: Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp Cell Res 26:260-268, 1962.
Puvion-Dutilleul F, Bachellerie J-P, Puvion E: Nucleolar organization of HeLa cells as studied by in situ hybridization. Chromosoma 100:395-409, 1991.
Puvion-Dutilleul F, Puvion E, Bachellerie J-P: Early stages of pre-rRNA formation within the nucleolar ultrastructure of mouse cells studied by in situ hybridization with 5'ETS leader probe. Chromosoma 105:496-505, 1997.
Roussel P, Andre C, Comai L, Hernandez-Verdun D: The rDNA transcription machinery is assembled during mitosis in active NORs and absent in inactive NORs. J Cell Biol 133:235-246, 1996.
Savino TM, Gebrane-Younes J, De Mey J, Sibarita J_B, Hernandez-Verdun D: Nucleolar assembly of the rRNA processing machinery in living cells. J Cell Biol 153:1097-1110, 2001.
Scheer U, Benavente R: Functional and dynamic aspects of the mammalian nucleolus. BioEssays 12:14-21, 1990.
Scheer U, Hock R: Structure and function of the nucleolus. Curr Opin Cell Biol 11:385-390, 1999.
Scheer U, Hugle B, Hazan R, Rose KM: Drug-induced dispersal of transcribed rRNA genes and transcriptional products: immunolocalization and silver staining of different nucleolar components in rat cells treated with 5,6-dichloro-beta-D-ribofuranosylbenzimidazole. J Cell Biol 99:672-679, 1984.
Scherl A, Coute Y, Deon C, Calle A, Kindbeiter K, Sanchez J-C, Greco A, Hochstrasser D, Diaz J-J: Functional proteomic analysis of human nucleolus. Molec Biol Cell 13:4100-4109, 2002.
Shaw PJ, Jordan EG: The nucleolus. Annu Rev Cell Dev Biol 11:93-121, 1995.
Shou W, Sakamoto KM, Keener J, Morimoto KW, Traverso EE, Azzam R, Hoppe GJ, Feldman RM, DeModena J, Moazed D, Charbonneau H, Nomura M, Deshaies RJ: Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit. Mol Cell 8:45-55, 2001.
Sirri V, Hernandez-Verdun D, Roussel P: Cyclin-dependent kinases govern formation and maintenance of the nucleolus. J Cell Biol 156:969-981, 2002.
Sirri V, Roussel P, Hernandez-Verdun D: The mitotically phosphorylated form of the transcription termination factor TTF-1 is associated with the repressed rDNA transcription machinery. J Cell Sci 112:3259-3268, 1999.
Sirri V, Roussel P, Hernandez-Verdun D: In vivo release of mitotic silencing of ribosomal gene transcription does not give rise to precursor ribosomal RNA processing. J Cell Biol 148:259-270, 2000.
Snaar S, Wiesmeijer K, Jochemsen AG, Tanke HJ, Dirks RW: Mutational analysis of fibrillarin and its mobility in living human cells. J Cell Biol 151:653-662, 2000.
Thiry M, Goessens G: The nucleolus during the cell cycle. In Molecular Biology Intelligence Unit. Springer-Verlag, Heidelberg 1996.
Thiry M, Thiry-Blaise L: Locating transcribed and non-transcribed rDNA spacer sequences within the nucleolus by in situ hybridization and immunoelectron microscopy. Nucleic Acids Res 19:11-15, 1991.
Trumtel S, Leger-Silvestre I, Gleizes P-E, Teulieres F, Gas N: Assembly and functional organization of the nucleolus: ultrastructural analysis of Saccharomyces cerevisiae mutants. Mol Biol Cell 11:2175-2189, 2000.
Tsai RYL, McKay RDG: A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes dev 16:2991-3003, 2002.
Verheggen C, Almouzni G, Hernandez-Verdun D: The ribosomal RNA processing machinery is recruited to the nucleolar domain before RNA polymerase I during Xenopus laevis development. J Cell Biol 149:293-305, 2000.
Visintin R, Amon A: The nucleolus: the magician's hat for cell cycle tricks. Curr Opin Cell Biol 12:372-377, 2000.
Weisenberger D, Scheer U: A possible mechanism for the inhibition of ribosomal RNA gene transcription during mitosis. J Cell Biol 129:561-575, 1995.
Gross MC, Schneider CH, Valente GT, Martins C, Feldberg E: Variability of 18S rDNA locus among Symphysodon fishes: chromosomal rearrangements. J Fish Biol 76:1117-1127, 2010.
Marin MP, Tomas M, Esteban-Pretel G, Megias L, Lopez-Iglesias C, Egea G, Renau-Piqueras J: Chronic ethanol exposure induces alterations in the nucleocytoplasmic transport in growing astrocytes. J Neurochem 106:1914-1928, 2008.
Berger J: A two-clock model of circadian timing in the immune system of mammals. Pathol Biol 56:286-291, 2008.
Berger J, Machackova M, Berger Z: Effects of feed restriction on the nucleolar structure and function in lymphocytes. Basic Clin Pharmacol Toxicol 97:236-237, 2005.