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• W1999962568 abstract "Cells typically respond quickly to stress, altering their metabolism to compensate. In mammalian cells, stress signaling usually leads to either cell-cycle arrest or apoptosis, depending on the severity of the insult and the ability of the cell to recover. Stress also often leads to reorganization of nuclear architecture, reflecting the simultaneous inhibition of major nuclear pathways (e.g., replication and transcription) and activation of specific stress responses (e.g., DNA repair). In this review, we focus on how two nuclear organelles, the nucleolus and the Cajal body, respond to stress. The nucleolus senses stress and is a central hub for coordinating the stress response. We review nucleolar function in the stress-induced regulation of p53 and the specific changes in nucleolar morphology and composition that occur upon stress. Crosstalk between nucleoli and CBs is also discussed in the context of stress responses. Cells typically respond quickly to stress, altering their metabolism to compensate. In mammalian cells, stress signaling usually leads to either cell-cycle arrest or apoptosis, depending on the severity of the insult and the ability of the cell to recover. Stress also often leads to reorganization of nuclear architecture, reflecting the simultaneous inhibition of major nuclear pathways (e.g., replication and transcription) and activation of specific stress responses (e.g., DNA repair). In this review, we focus on how two nuclear organelles, the nucleolus and the Cajal body, respond to stress. The nucleolus senses stress and is a central hub for coordinating the stress response. We review nucleolar function in the stress-induced regulation of p53 and the specific changes in nucleolar morphology and composition that occur upon stress. Crosstalk between nucleoli and CBs is also discussed in the context of stress responses. The main function of the nucleolus is the rapid production of small and large ribosome subunits, a process that must be highly regulated to achieve proper cellular proliferation and cell growth (Lempiainen and Shore, 2009Lempiainen H. Shore D. Growth control and ribosome biogenesis.Curr. Opin. Cell Biol. 2009; 21: 855-863Crossref PubMed Scopus (93) Google Scholar). Many aspects of nucleolar organization and function are conserved within eukaryotic organisms, from yeast to human (Kressler et al., 2010Kressler D. Hurt E. Bassler J. Driving ribosome assembly.Biochim. Biophys. Acta. 2010; 1803: 673-683Crossref PubMed Scopus (126) Google Scholar). This review focuses on how stress responses in mammalian cells affect the nucleolus and Cajal bodies (CBs), and we introduce this topic by giving a brief overview of ribosome subunit biogenesis in mammalian cells. For an overview of the related processes of ribosome subunit biogenesis in yeast, we refer the reader to the following reviews: Henras et al., 2008Henras A.K. Soudet J. Gerus M. Lebaron S. Caizergues-Ferrer M. Mougin A. Henry Y. The post-transcriptional steps of eukaryotic ribosome biogenesis.Cell. Mol. Life Sci. 2008; 65: 2334-2359Crossref PubMed Scopus (257) Google Scholar and Tschochner and Hurt, 2003Tschochner H. Hurt E. Pre-ribosomes on the road from the nucleolus to the cytoplasm.Trends Cell Biol. 2003; 13: 255-263Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar. Nucleoli in mammalian cells disassemble when cells divide and reform at the end of mitosis around the tandemly repeated clusters of rDNA genes known as nucleolar organizing regions (NORs). This results in a subnuclear compartment that concentrates the factors involved in ribosomal RNA (rRNA) transcription and processing, as well as ribosome subunit assembly (for detailed review, see Kressler et al., 2010Kressler D. Hurt E. Bassler J. Driving ribosome assembly.Biochim. Biophys. Acta. 2010; 1803: 673-683Crossref PubMed Scopus (126) Google Scholar). Transcription of rDNA genes by RNA polymerase I (RNA Pol I) leads to the synthesis of a 47S precursor ribosomal RNA transcript (pre-rRNA). The pre-rRNA is either co- or posttranscriptionally processed and modified by snoRNPs (small nucleolar ribonucleoproteins) to generate the 28S, 18S, and 5.8S rRNAs. These snoRNP-mediated modifications include 2′-O-methylation and pseudouridine formation (Matera et al., 2007Matera A.G. Terns R.M. Terns M.P. Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs.Nat. Rev. Mol. Cell Biol. 2007; 8: 209-220Crossref PubMed Scopus (260) Google Scholar). The 28S, 18S, and 5.8S rRNAs are assembled with ribosomal proteins (RPs) to form the small and large preribosome subunits, which are each exported separately to the cytoplasm and undergo final processing steps to become the mature 40S and 60S ribosome subunits. The three main events that occur within the nucleolus—pre-rRNA transcription, processing, and ribosomal RNP assembly—are reflected in its “tripartite” internal structure. These events, or at least the molecules that mediate them, are concentrated in three distinct subnucleolar compartments called the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC), as summarized in Figure 1A . It is generally accepted that pre-rRNA is transcribed from rDNA either in the FC or at the border between the FC and DFC. FCs are enriched in components of the RNA Pol I machinery, such as UBF, whereas the DFC harbors pre-rRNA processing factors, such as the snoRNAs and snoRNP proteins, fibrillarin and Nop58. Both the FC and the DFC are enclosed by the GC, where preribosome subunit assembly takes place (reviewed in Boisvert et al., 2007Boisvert F.M. van Koningsbruggen S. Navascues J. Lamond A.I. The multifunctional nucleolus.Nat. Rev. Mol. Cell Biol. 2007; 8: 574-585Crossref PubMed Scopus (500) Google Scholar, Sirri et al., 2008Sirri V. Urcuqui-Inchima S. Roussel P. Hernandez-Verdun D. Nucleolus: the fascinating nuclear body.Histochem. Cell Biol. 2008; 129: 13-31Crossref PubMed Scopus (149) Google Scholar) (Figure 1B). The morphology and size of nucleoli are linked to nucleolar activity, which in turn depends on cell growth and metabolism. The varied effects on ribosome subunit production and cell growth induced by different types of cellular stress are often accompanied by dramatic changes in the organization and composition of the nucleolus (Table 1). A well-described phenomenon is the nucleolar segregation caused by DNA damage (e.g., following UV irradiation or inhibition of topoisomerase II by drugs such as etoposide) and/or transcriptional inhibition (e.g., by actinomycin D) (Al-Baker et al., 2005Al-Baker E.A. Oshin M. Hutchison C.J. Kill I.R. Analysis of UV-induced damage and repair in young and senescent human dermal fibroblasts using the comet assay.Mech. Ageing Dev. 2005; 126: 664-672Crossref PubMed Scopus (9) Google Scholar, Govoni et al., 1994Govoni M. Farabegoli F. Pession A. Novello F. Inhibition of topoisomerase II activity and its effect on nucleolar structure and function.Exp. Cell Res. 1994; 211: 36-41Crossref PubMed Scopus (9) Google Scholar). Segregation is characterized by the condensation and subsequent separation of the FC and GC, together with the formation of “nucleolar caps” around the nucleolar remnant (also called central body) (Shav-Tal et al., 2005Shav-Tal Y. Blechman J. Darzacq X. Montagna C. Dye B.T. Patton J.G. Singer R.H. Zipori D. Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition.Mol. Biol. Cell. 2005; 16: 2395-2413Crossref PubMed Scopus (120) Google Scholar). Different types of caps are formed by nucleolar proteins such as UBF (Figure 1C), nucleoplasmic proteins (mostly RNA-binding proteins), and the CB marker, coilin. Importantly, nucleolar segregation is different from the process of nucleolar fragmentation, which occurs following inhibition of either RNA Pol II (but not I) or protein kinases (David-Pfeuty, 1999David-Pfeuty T. Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells.Oncogene. 1999; 18: 7409-7422Crossref PubMed Google Scholar, Haaf and Ward, 1996Haaf T. Ward D.C. Inhibition of RNA polymerase II transcription causes chromatin decondensation, loss of nucleolar structure, and dispersion of chromosomal domains.Exp. Cell Res. 1996; 224: 163-173Crossref PubMed Scopus (110) Google Scholar) and leads to unravelling of the FC (Figure 1C). Viral infections can also cause specific changes in nucleolar morphology, such as an increase in nucleolar and/or FC size following corona virus infection (reviewed in Greco, 2009Greco A. Involvement of the nucleolus in replication of human viruses.Rev. Med. Virol. 2009; 19: 201-214Crossref PubMed Scopus (34) Google Scholar, Hiscox, 2007Hiscox J.A. RNA viruses: hijacking the dynamic nucleolus.Nat. Rev. Microbiol. 2007; 5: 119-127Crossref PubMed Scopus (134) Google Scholar).Table 1Summary of the Effects of Different Stress Types on Nucleolar and CB OrganizationStress TypeTriggerp53 StabilizationEffects on NucleolusEffects on CBsReferencesDNA damage/genotoxic stressUV-C✓Nucleolar segregation, delocalization of Ki-67CB disruption and coilin in nucleoplasmic microfociRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Al-Baker et al., 2005Al-Baker E.A. Oshin M. Hutchison C.J. Kill I.R. Analysis of UV-induced damage and repair in young and senescent human dermal fibroblasts using the comet assay.Mech. Ageing Dev. 2005; 126: 664-672Crossref PubMed Scopus (9) Google Scholar, Cioce et al., 2006Cioce M. Boulon S. Matera A.G. Lamond A.I. UV-induced fragmentation of Cajal bodies.J. Cell Biol. 2006; 175: 401-413Crossref PubMed Scopus (38) Google ScholarIR (DSB)✓Nucleolar disruption, ATM-dependent inhibition of RNA pol I activityNo major effect on coilin distributionRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Kruhlak et al., 2007Kruhlak M. Crouch E.E. Orlov M. Montano C. Gorski S.A. Nussenzweig A. Misteli T. Phair R.D. Casellas R. The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks.Nature. 2007; 447: 730-734Crossref PubMed Scopus (78) Google ScholarCamptothecin Bleomycin✓Nucleolar disruptionN/ARubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google ScholarTemperature changeHeat shock✓Nucleolar disruptionCBs smaller at 39°C; micro-CBs in XenopusRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Carmo-Fonseca et al., 1993Carmo-Fonseca M. Ferreira J. Lamond A.I. Assembly of snRNP-containing coiled bodies is regulated in interphase and mitosis—evidence that the coiled body is a kinetic nuclear structure.J. Cell Biol. 1993; 120: 841-852Crossref PubMed Google Scholar, Handwerger et al., 2002Handwerger K.E. Wu Z. Murphy C. Gall J.G. Heat shock induces mini-Cajal bodies in the Xenopus germinal vesicle.J. Cell Sci. 2002; 115: 2011-2020PubMed Google ScholarCold shockCBs bigger at 32°CCarmo-Fonseca et al., 1993Carmo-Fonseca M. Ferreira J. Lamond A.I. Assembly of snRNP-containing coiled bodies is regulated in interphase and mitosis—evidence that the coiled body is a kinetic nuclear structure.J. Cell Biol. 1993; 120: 841-852Crossref PubMed Google ScholarHypoxia–✓Nucleolar disruption, VHL-dependent reduction of rRNA transcriptionN/ARubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Mekhail et al., 2006Mekhail K. Rivero-Lopez L. Khacho M. Lee S. Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia.Cell Cycle. 2006; 5: 2401-2413Crossref PubMed Google ScholarOsmotic stressN/AN/ADisruption of CBsCioce et al., 2006Cioce M. Boulon S. Matera A.G. Lamond A.I. UV-induced fragmentation of Cajal bodies.J. Cell Biol. 2006; 175: 401-413Crossref PubMed Scopus (38) Google ScholarViral infectionAdenovirus, Coronavirus, HCV, HIV, HPV, HSV-1, Poliovirus, West Nile virusN/AChanges in nucleolar morphology and proteomeCoilin in nucleoplasmic microfoci and rosettes (adenovirus); ICP0-induced accumulation of coilin at damaged centromeres (HSV-1)Greco, 2009Greco A. Involvement of the nucleolus in replication of human viruses.Rev. Med. Virol. 2009; 19: 201-214Crossref PubMed Scopus (34) Google Scholar, Rebelo et al., 1996Rebelo L. Almeida F. Ramos C. Bohmann K. Lamond A.I. Carmo-Fonseca M. The dynamics of coiled bodies in the nucleus of adenovirus-infected cells.Mol. Biol. Cell. 1996; 7: 1137-1151Crossref PubMed Google Scholar, James et al., 2010James N.J. Howell G.J. Walker J.H. Blair G.E. The role of Cajal bodies in the expression of late phase adenovirus proteins.Virology. 2010; 399: 299-311Crossref PubMed Scopus (7) Google Scholar, Morency et al., 2007Morency E. Sabra M. Catez F. Texier P. Lomonte P. A novel cell response triggered by interphase centromere structural instability.J. Cell Biol. 2007; 177: 757-768Crossref PubMed Scopus (27) Google ScholarNutrient stressSerum starvationN/AReduction in ribosomal biogenesisCB number decreasesMayer and Grummt, 2006Mayer C. Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases.Oncogene. 2006; 25: 6384-6391Crossref PubMed Scopus (162) Google Scholar, Murayama et al., 2008Murayama A. Ohmori K. Fujimura A. Minami H. Yasuzawa-Tanaka K. Kuroda T. Oie S. Daitoku H. Okuwaki M. Nagata K. et al.Epigenetic control of rDNA loci in response to intracellular energy status.Cell. 2008; 133: 627-639Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, Hoppe et al., 2009Hoppe S. Bierhoff H. Cado I. Weber A. Tiebe M. Grummt I. Voit R. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply.Proc. Natl. Acad. Sci. USA. 2009; 106: 17781-17786Crossref PubMed Scopus (49) Google Scholar, Zhou et al., 2009Zhou Y. Schmitz K.M. Mayer C. Yuan X. Akhtar A. Grummt I. Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing.Nat. Cell Biol. 2009; 11: 1010-1016Crossref PubMed Scopus (42) Google Scholar, Tanaka et al., 2010Tanaka Y. Okamoto K. Teye K. Umata T. Yamagiwa N. Suto Y. Zhang Y. Tsuneoka M. JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation.EMBO J. 2010; 29: 1510-1522Crossref PubMed Scopus (27) Google Scholar, Andrade et al., 1993Andrade L.E. Tan E.M. Chan E.K. Immunocytochemical analysis of the coiled body in the cell cycle and during cell proliferation.Proc. Natl. Acad. Sci. USA. 1993; 90: 1947-1951Crossref PubMed Google ScholarInhibition of RNA polymerase I and/or IIActinomycin D✓Nucleolar disruption, release of RPs into the nucleoplasmCoilin in nucleolar capsLindstrom, 2009Lindstrom M.S. Emerging functions of ribosomal proteins in gene-specific transcription and translation.Biochem. Biophys. Res. Commun. 2009; 379: 167-170Crossref PubMed Scopus (62) Google Scholar, Warner and McIntosh, 2009Warner J.R. McIntosh K.B. How common are extraribosomal functions of ribosomal proteins?.Mol. Cell. 2009; 34: 3-11Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, Zhang and Lu, 2009Zhang Y. Lu H. Signaling to p53: ribosomal proteins find their way.Cancer Cell. 2009; 16: 369-377Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, Carmo-Fonseca et al., 1992Carmo-Fonseca M. Pepperkok R. Carvalho M.T. Lamond A.I. Transcription-dependent colocalization of the U1, U2, U4/U6, and U5 snRNPs in coiled bodies.J. Cell Biol. 1992; 117: 1-14Crossref PubMed Scopus (238) Google Scholar, Shav-Tal et al., 2005Shav-Tal Y. Blechman J. Darzacq X. Montagna C. Dye B.T. Patton J.G. Singer R.H. Zipori D. Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition.Mol. Biol. Cell. 2005; 16: 2395-2413Crossref PubMed Scopus (120) Google ScholarDRB✓Nucleolar disruptionNucleolar association of coilinRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholarα-Amanitin✓Nucleolar disruptionCoilin in cap-like structures associated with the nucleolusRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Carmo-Fonseca et al., 1992Carmo-Fonseca M. Pepperkok R. Carvalho M.T. Lamond A.I. Transcription-dependent colocalization of the U1, U2, U4/U6, and U5 snRNPs in coiled bodies.J. Cell Biol. 1992; 117: 1-14Crossref PubMed Scopus (238) Google ScholarInhibition of nuclear exportLeptomycin B (LMB)✓No disruption of nucleolar integrityNucleolar association of coilinRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Sleeman et al., 2001Sleeman J.E. Ajuh P. Lamond A.I. snRNP protein expression enhances the formation of Cajal bodies containing p80-coilin and SMN.J. Cell Sci. 2001; 114: 4407-4419PubMed Google ScholarInhibition of phosphatasesOkadaic acidN/AN/AAccumulation of coilin in the nucleolusLyon et al., 1997Lyon C.E. Bohmann K. Sleeman J. Lamond A.I. Inhibition of protein dephosphorylation results in the accumulation of splicing snRNPs and coiled bodies within the nucleolus.Exp. Cell Res. 1997; 230: 84-93Crossref PubMed Scopus (95) Google ScholarInhibition of DNA and RNA synthesis5-Fluorouracil✓Nucleolar disruption, release of RPs into the nucleoplasm and p53 stabilisation. rRNA processing disrupted in the nucleolusN/ALindstrom, 2009Lindstrom M.S. Emerging functions of ribosomal proteins in gene-specific transcription and translation.Biochem. Biophys. Res. Commun. 2009; 379: 167-170Crossref PubMed Scopus (62) Google Scholar, Warner and McIntosh, 2009Warner J.R. McIntosh K.B. How common are extraribosomal functions of ribosomal proteins?.Mol. Cell. 2009; 34: 3-11Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, Zhang and Lu, 2009Zhang Y. Lu H. Signaling to p53: ribosomal proteins find their way.Cancer Cell. 2009; 16: 369-377Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, Burger et al., 2010Burger K. Muhl B. Harasim T. Rohrmoser M. Malamoussi A. Orban M. Kellner M. Gruber-Eber A. Kremmer E. Holzel M. Eick D. Chemotherapeutic drugs inhibit ribosome biogenesis at various levels.J. Biol. Chem. 2010; 285: 12416-12425Crossref PubMed Scopus (67) Google ScholarAlteration of proteasome activityMG132✓No disruption of nucleolar integrity, inhibition of late rRNA processingNo disruption of CBsRubbi and Milner, 2003Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.EMBO J. 2003; 22: 6068-6077Crossref PubMed Scopus (407) Google Scholar, Burger et al., 2010Burger K. Muhl B. Harasim T. Rohrmoser M. Malamoussi A. Orban M. Kellner M. Gruber-Eber A. Kremmer E. Holzel M. Eick D. Chemotherapeutic drugs inhibit ribosome biogenesis at various levels.J. Biol. Chem. 2010; 285: 12416-12425Crossref PubMed Scopus (67) Google Scholar; personal observationOverexpression of PA28γN/AN/ADisruption of CBsCioce et al., 2006Cioce M. Boulon S. Matera A.G. Lamond A.I. UV-induced fragmentation of Cajal bodies.J. Cell Biol. 2006; 175: 401-413Crossref PubMed Scopus (38) Google ScholarAlteration of snRNP biogenesisDepletion of SMN, PHAX, TGS1N/AN/ADisruption of CBs and nucleolar localization of coilinLemm et al., 2006Lemm I. Girard C. Kuhn A.N. Watkins N.J. Schneider M. Bordonne R. Luhrmann R. Ongoing U snRNP biogenesis is required for the integrity of Cajal bodies.Mol. Biol. Cell. 2006; 17: 3221-3231Crossref PubMed Scopus (85) Google ScholarSmB overexpressionN/AIncrease in CB numberSleeman et al., 2001Sleeman J.E. Ajuh P. Lamond A.I. snRNP protein expression enhances the formation of Cajal bodies containing p80-coilin and SMN.J. Cell Sci. 2001; 114: 4407-4419PubMed Google ScholarOncogenic stressc-myc or Ras activation✓Up regulation of nucleolar proteins p14ARF and B23/NPMN/AKruse and Gu, 2009Kruse J.P. Gu W. Modes of p53 regulation.Cell. 2009; 137: 609-622Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, Lee and Gu, 2010Lee J.T. Gu W. The multiple levels of regulation by p53 ubiquitination.Cell Death Differ. 2010; 17: 86-92Crossref PubMed Scopus (94) Google Scholar, Chen et al., 2010Chen D. Shan J. Zhu W.G. Qin J. Gu W. Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses.Nature. 2010; 464: 624-627Crossref PubMed Scopus (52) Google ScholarAlteration of ribosome subunit biogenesisMalfunction of nucleolar proteins (e.g., Bop1, B23/NPM, nucleostemin)✓Release of RPs into the nucleoplasm following, in most cases, nucleolar disruption.N/AFumagalli et al., 2009Fumagalli S. Di Cara A. Neb-Gulati A. Natt F. Schwemberger S. Hall J. Babcock G.F. Bernardi R. Pandolfi P.P. Thomas G. Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction.Nat. Cell Biol. 2009; 11: 501-508Crossref PubMed Scopus (128) Google Scholar, Lindstrom, 2009Lindstrom M.S. Emerging functions of ribosomal proteins in gene-specific transcription and translation.Biochem. Biophys. Res. Commun. 2009; 379: 167-170Crossref PubMed Scopus (62) Google Scholar, Warner and McIntosh, 2009Warner J.R. McIntosh K.B. How common are extraribosomal functions of ribosomal proteins?.Mol. Cell. 2009; 34: 3-11Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, Zhang and Lu, 2009Zhang Y. Lu H. Signaling to p53: ribosomal proteins find their way.Cancer Cell. 2009; 16: 369-377Abstract Full Text Full Text PDF PubMed Scopus (175) Google ScholarRP knockdownIR, gamma irradiation; DSB, double-strand breaks; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus type 1; RP, ribosomal proteins; N/A, not available. Open table in a new tab IR, gamma irradiation; DSB, double-strand breaks; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus type 1; RP, ribosomal proteins; N/A, not available. Efficient ribosome subunit biogenesis is central to gene expression and is also a highly energy-consuming process that is tightly coupled to cell growth, i.e., the ability of a cell to achieve a certain cell mass before cell division can occur. A high transcription rate of rDNA genes and the activity of all three RNA polymerases is required in animal cells undergoing rapid proliferation to meet the cellular demand for ribosomes. Under stress conditions that affect cell-cycle progression and/or intracellular energy status, such as nutrient deprivation, alteration of ribosome subunit biosynthesis is one strategy that can preserve cellular energy homeostasis (Sengupta et al., 2010Sengupta S. Peterson T.R. Sabatini D.M. Regulation of the mTor complex 1 by nutrients, growth factors, and stress.Mol. Cell. 2010; 40 (this issue): 310-322Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar). This can occur at several different levels, which include regulation of RNA Pol I transcription and/or rRNA processing (reviewed in Chedin et al., 2007Chedin S. Laferte A. Hoang T. Lafontaine D.L. Riva M. Carles C. Is ribosome synthesis controlled by pol I transcription?.Cell Cycle. 2007; 6: 11-15Crossref PubMed Google Scholar, Grummt and Voit, 2010Grummt I. Voit R. Linking rDNA transcription to the cellular energy supply.Cell Cycle. 2010; 9: 225-226Crossref PubMed Scopus (9) Google Scholar). Only ∼50% of the ∼400 rDNA repeats in the human diploid genome are transcriptionally active. Interestingly, a change in growth conditions predominantly triggers a change in the transcriptional efficiency of already active genes, rather than the activation of silent genes (reviewed in McStay and Grummt, 2008McStay B. Grummt I. The epigenetics of rRNA genes: from molecular to chromosome biology.Annu. Rev. Cell Dev. Biol. 2008; 24: 131-157Crossref PubMed Scopus (173) Google Scholar, Moss et al., 2007Moss T. Langlois F. Gagnon-Kugler T. Stefanovsky V. A housekeeper with power of attorney: the rRNA genes in ribosome biogenesis.Cell. Mol. Life Sci. 2007; 64: 29-49Crossref PubMed Scopus (97) Google Scholar). The basal transcription factors, TIF-1A, SL1, and UBF, are essential for transcription by RNA Pol I and appear to be modulated by different signaling pathways in response to changes in environmental conditions (reviewed in Grummt, 2003Grummt I. Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus.Genes Dev. 2003; 17: 1691-1702Crossref PubMed Scopus (271) Google Scholar). A key player for the regulation of ribosomal synthesis in response to extracellular conditions is the kinase mammalian target of rapamycin (mTOR), which promotes pre-rRNA synthesis by regulating the localization and/or activity of TIF-1A, SL1, and UBF, as well as translation of RPs (Mayer and Grummt, 2006Mayer C. Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases.Oncogene. 2006; 25: 6384-6391Crossref PubMed Scopus (162) Google Scholar, Xiao and Grove, 2009Xiao L. Grove A. Coordination of ribosomal protein and ribosomal RNA gene expression in response to TOR signaling.Curr. Genomics. 2009; 10: 198-205Crossref PubMed Scopus (19) Google Scholar). mTOR inactivation either by nutrient deprivation or treatment of cells with the specific mTOR inhibitor rapamycin leads to reduced pre-rRNA transcription and thereby decreased ribosome subunit production. Although the mechanisms for starvation-induced inactivation of mTOR are not completely understood, mTOR activity is inhibited by an increase in the cellular AMP/ATP ratio upon nutrient deprivation, via activation of the LKB1-AMPK pathway (Hardie, 2005Hardie D.G. New roles for the LKB1→AMPK pathway.Curr. Opin. Cell Biol. 2005; 17: 167-173Crossref PubMed Scopus (177) Google Scholar, Sengupta et al., 2010Sengupta S. Peterson T.R. Sabatini D.M. Regulation of the mTor complex 1 by nutrients, growth factors, and stress.Mol. Cell. 2010; 40 (this issue): 310-322Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar). Overall, a complex signaling network that integrates mTOR, PI3K (phosphatidylinositol 3-kinase), and MAPK (mitogen-activated protein kinase) pathways is involved in the regulation of ribosome subunit production in response either to changes in nutrient levels, or to growth factor signaling such as IGF-1 (insulin-like growth factor 1) signaling (James and Zomerdijk, 2004James M.J. Zomerdijk J.C. Phosphatidylinositol 3-kinase and mTOR signaling pathways regulate RNA polymerase I transcription in response to IGF-1 and nutrients.J. Biol. Chem. 2004; 279: 8911-8918Crossref PubMed Scopus (63) Google Scholar). DNA damage, such as chromosomal double-strand breaks, transiently reduces RNA Pol I transcription in MEFs in an ATM-dependent manner, by interfering with initiation complex assembly and impairing efficient transcription elongation (Kruhlak et al., 2007Kruhlak M. Crouch E.E. Orlov M. Montano C. Gorski S.A. Nussenzweig A. Misteli T. Phair R.D. Casellas R. The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks.Nature. 2007; 447: 730-734Crossref PubMed Scopus (78) Google Scholar). rRNA synthesis is also decreased during hypoxia in a process requiring the interaction of the von Hippel-Lindau (vHL) tumor suppressor protein with the rDNA promoter (Mekhail et al., 2006Mekhail K. Rivero-Lopez L. Khacho M. Lee S. Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia.Cell Cycle. 2006; 5: 2401-2413Crossref PubMed Google Scholar). Interestingly, viral infection can either inhibit or promote the host's pre-RNA synthesis. For example, poliovirus inhibits RNA Pol I activity by inducing SL1 cleavage and UBF posttranslational modification (Banerjee et al., 2005Banerjee R. Weidman M.K. Navarro S. Comai L. Dasgupta A. Modifications of both selectivity factor and upstream binding factor contribute to poliovirus-mediated inhibition of RNA polymerase I transcription.J. Gen. Virol. 2005; 86: 2315-2322Crossref PubMed Scopus (14) Google Scholar), while hepatitis C virus stimulates RNA Pol I activity, thereby promoting liver carcinogenesis (Kao et al., 2004Kao C.F. Chen S.Y. Lee Y.H. Activation of RNA polymerase I transcription by hepatitis C virus core protein.J. Biomed. Sci. 2004; 11: 72-94Crossref PubMed Google Scholar). Despite the consensus that stress-dependent regulation of pre-rRNA synthesis mainly occurs by influencing the transcriptional rate of already active genes, recent findings also point toward additional regulatory pathways, such as epigenetic regulation of rRNA transcription. For example, protein complexes whose activities are responsive to intracellular energy status, including eNoSC and NoRC, as well as the JmjC histone demethylase KDM2A, can induce the formation of transcriptionally silent heterochromatin in the nucleolus by triggering" @default.
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