[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

The nucleolus—guardian of cellular homeostasis and genome integrity

  • Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

All organisms sense and respond to conditions that stress their homeostasis by downregulating the synthesis of rRNA and ribosome biogenesis, thus designating the nucleolus as the central hub in coordinating the cellular stress response. One of the most intriguing roles of the nucleolus, long regarded as a mere ribosome-producing factory, is its participation in monitoring cellular stress signals and transmitting them to the RNA polymerase I (Pol I) transcription machinery. As rRNA synthesis is a most energy-consuming process, switching off transcription of rRNA genes is an effective way of saving the energy required to maintain cellular homeostasis during acute stress. The Pol I transcription machinery is the key convergence point that collects and integrates a vast array of information from cellular signaling cascades to regulate ribosome production which, in turn, guides cell growth and proliferation. This review focuses on the mechanisms that link cell physiology to rDNA silencing, a prerequisite for nucleolar integrity and cell survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ahmad Y, Boisvert FM, Gregor P, Lamond AI (2009) NOPdb: nucleolar proteome database—2008 update. Nucleic Acids Res 37:D181–D184

    Article  PubMed  CAS  Google Scholar 

  • Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M (2005) Nucleolar proteome dynamics. Nature 433(7021):77–83

    Article  PubMed  CAS  Google Scholar 

  • Audas TE, Jacob MD, Lee S (2012) Immobilization of proteins in the nucleolus by ribosomal intergenic spacer noncoding RNA. Mol Cell 45:147–157

    Article  PubMed  CAS  Google Scholar 

  • Banski P, Kodiha M, Stochai U (2010) Chaperones and multitasking proteins in the nucleolus: networking together for survival? Trends Biochem Sci 35:361–367

    Article  PubMed  CAS  Google Scholar 

  • Boisvert FM, Lamond AI (2010) p53-Dependent subcellular proteome localization following DNA damage. Proteomics 10:4087–4097

    Article  PubMed  CAS  Google Scholar 

  • Barber M, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen R, Paredes S, Young N, Chen K et al (2012) SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487:114–118

    PubMed  CAS  Google Scholar 

  • Boulon S, Westman B, Hutten S, Boisvert SF-M, Lamond AI (2010) The nucleolus under stress. Mol Cell 40:216–227

    Article  PubMed  CAS  Google Scholar 

  • Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, Wall M, Cluse L et al (2012) Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22:51–65

    Article  PubMed  CAS  Google Scholar 

  • Carson DA, Lois A (1995) Cancer progression and p53. Lancet 346:1009–1011

    Article  PubMed  CAS  Google Scholar 

  • Chen Y-R, Wang X, Templeton D, Davis RJ, Tan T-H (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and radiation. J Biol Chem 271:31929–31936

    Article  PubMed  CAS  Google Scholar 

  • Chen S, Seiler J, Santiago-Reichelt M, Felbel M, Grummt I, Voit R (2013) Interaction of SIRT7 with nascent RNA mediates deacetylation of PAF53 and confers stress response to RNA polymerase I transcription. Mol Cell, in press

  • Clos J, Buttgereit D, Grummt I (1986) A purified transcription factor (TIF-IB) binds to essential sequences of the mouse rDNA promoter. Proc Natl Acad Sci U S A 83:604–608

    Article  PubMed  CAS  Google Scholar 

  • Comai L, Tanese N, Tjian R (1992) The TATA-binding protein and associated factors are integral components of the RNA polymerase I transcription factor, SL1. Cell 68:965–976

    Article  PubMed  CAS  Google Scholar 

  • Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  PubMed  CAS  Google Scholar 

  • Denissov S, van Driel M, Voit R, Hekkelman M, Hulsen T, Hernandez N, Grummt I, Wehrens R, Stunnenberg H (2007) Identification of novel functional TBP-binding sites and general factor repertoires. EMBO J 26:944–954

    Article  PubMed  CAS  Google Scholar 

  • Drygin D, Rice WG, Grummt I (2010) The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer. Ann Rev Pharm Tox 50:131–156

    Article  CAS  Google Scholar 

  • Dundr M, Hoffmann-Rohrer U, Hu Q, Grummt I, Rothblum LI, Phair RD, Misteli T (2002) A kinetic framework for a mammalian RNA polymerase in vivo. Science 298:1623–1626

    Article  PubMed  CAS  Google Scholar 

  • Feige J, Auwerx J (2007) Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol 17:292–300

    Article  PubMed  CAS  Google Scholar 

  • Feige J, Auwerx (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20:303–309

    Article  PubMed  CAS  Google Scholar 

  • Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L (2006) Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev 20:1075–1080

    Article  PubMed  CAS  Google Scholar 

  • Gorski JJ, Pathak S, Panov K, Kasciukovic T, Panova T, Russell J, Zomerdijk JCBM (2007) A novel TBP-associated factor of SL1 functions in RNA polymerase I transcription. EMBO J 26:1560–1568

    Article  PubMed  CAS  Google Scholar 

  • Govoni M, Farabegoli F, Pession A, Novello F (1994) Inhibition of topoisomerase II activity and its effect on nucleolar structure and function. Exp Cell Res 211:36–41

    Article  PubMed  CAS  Google Scholar 

  • Grob A, Roussel P, Wright JE, McStay B, Hernandez-Verdun D, Sirri V (2009) Involvement of SIRT7 in resumption of rDNA transcription at the exit from mitosis. J Cell Sci 122:489–498

    Article  PubMed  CAS  Google Scholar 

  • Grummt I (2003) Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev 17:1691–1702

    Article  PubMed  CAS  Google Scholar 

  • Grummt I (2010) Wisely chosen paths: regulation of ribosomal RNA synthesis. FEBS J 277:4626–4639

    Article  PubMed  CAS  Google Scholar 

  • Grummt I, Grummt F (1976) Control of nucleolar RNA synthesis by the intracellular pool sizes of ATP and GTP. Cell 7:447–453

    Article  PubMed  CAS  Google Scholar 

  • Grummt I, Längst G (2013) Epigenetic control of RNA polymerase I transcription in mammalian cells. Biochim Biophys Acta-Gene Regulatory Mechanisms 1829:393–404

    Article  CAS  Google Scholar 

  • Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Ann Rev Pathol 5:253–295

    Article  CAS  Google Scholar 

  • Hanada KI, Song CZ, Yamamoto K, Yano KI, Maedal Y, Yamaguchi K, Muramatsu M (1996) RNA polymerase I associated factor 53 binds to the nucleolar transcription factor UBF and functions in specific rDNA transcription. EMBO J 15:2217–2226

    PubMed  CAS  Google Scholar 

  • Heix J, Zomerdijk JCBM, Ravanpay A, Tjian R, Grummt I (1997) Cloning of murine RNA polymerase I-specific TAFs: conserved interactions between the four subunits of the species-specific transcription factor TIF-IB/SL1. Proc Natl Acad Sci U S A 94:1733–1738

    Article  PubMed  CAS  Google Scholar 

  • Hiscox JA, Whitehouse A, Matthews DA (2010) Nucleolar proteomics and viral infection. Proteomics 10:4077–4086

    Article  PubMed  CAS  Google Scholar 

  • Hoppe S, Bierhoff H, Cado I, Weber A, Tiebe M, Grummt I, Voit R (2009) AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc Natl Acad Sci U S A 106:17781–17786

    Article  PubMed  CAS  Google Scholar 

  • Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13:225–238

    PubMed  CAS  Google Scholar 

  • Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31:212–220

    Article  PubMed  CAS  Google Scholar 

  • Jantzen HM, Admon A, Bell SP, Tjian R (1990) Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature 344:830–836

    Article  PubMed  CAS  Google Scholar 

  • Kar B, Liu B, Zhou Z, Lam YW (2011) Quantitative nucleolar proteomics reveals nuclear re-organization during stress-induced senescence in mouse fibroblasts. BMC Cell Biol 12:33

    Article  PubMed  CAS  Google Scholar 

  • Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, Chang YG, Shen Q, Park WS, Lee JY, Borlak J, Nam SW (2013) Sirtuin oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125b. Hepatology 57:1055–1067

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi T, Ganley AR (2005) Recombination regulation by transcription-induced cohesion dissociation in rDNA repeats. Science 309:1581–1584

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi T (2008) A new role of the rDNA and nucleolus in the nucleus—rDNA instability maintains genome integrity. BioEssays 30:267–272

    Article  PubMed  CAS  Google Scholar 

  • Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M (2004) Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5:465–475

    Article  PubMed  CAS  Google Scholar 

  • Lam YW, Evans VC, Heesom KJ, Lamond AI, Matthews DA (2010) Proteomics analysis of the nucleolus in adenovirus-infected cells. Mol Cell Proteomics 9:117–130

    Article  PubMed  CAS  Google Scholar 

  • Learned RM, Cordes S, Tjian R (1985) Purification and characterization of a transcription factor that confers promoter specificity to human RNA polymerase I. Mol Cell Biol 5:1358–1369

    PubMed  CAS  Google Scholar 

  • Mayer C, Grummt I (2005) Cellular stress and nucleolar function. Cell Cycle 4:1036–1038

    Article  PubMed  CAS  Google Scholar 

  • Mayer C, Zhao J, Yuan X, Grummt I (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18:423–434

    Article  PubMed  CAS  Google Scholar 

  • Mayer C, Bierhoff H, Grummt I (2006) The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes Dev 19:933–941

    Article  Google Scholar 

  • McStay B, Grummt I (2008) The epigenetics of rRNA genes: from molecular to chromosome biology. Annu Rev Cell Dev Biol 24:131–157

    Article  PubMed  CAS  Google Scholar 

  • Mekhail K, Khacho M, Carrigan A, Hache RR, Gunaratnam L, Lee S (2005) Regulation of ubiquitin ligase dynamics by the nucleolus. J Cell Biol 170:733–744

    Article  PubMed  CAS  Google Scholar 

  • Moss T, Langlois F, Gagnon-Kugler T, Stefanovsky V (2007) A housekeeper with power of attorney: the rRNA genes in ribosome biogenesis. Cell Mol Life Sci 64:29–49

    Article  PubMed  CAS  Google Scholar 

  • Muth V, Nadaud S, Grummt I, Voit R (2001) Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription. EMBO J 20:1353–1362

    Article  PubMed  CAS  Google Scholar 

  • Murayama A, Ohmor K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, KimuraK K, Shimizu T, Yanagisawa J (2008) Epigenetic control of rDNA loci in response to intracellular energy status. Cell 133:627–639

    Article  PubMed  CAS  Google Scholar 

  • Olson MO (2004) Sensing cellular stress: another new function of the nucleolus? Sci STKE 224:pe10. doi:10.1126/stke.2242004pe10

    Google Scholar 

  • Peng JC, Karpen GH (2007) H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat Cell Biol 9:25–35

    Article  PubMed  CAS  Google Scholar 

  • Peng JC, Karpen GH (2008) Epigenetic regulation of heterochromatic DNA stability. Curr Opin Genet Dev 18:204–211

    Article  PubMed  CAS  Google Scholar 

  • Peng JC, Karpen GH (2009) Heterochromatic genome stability requires regulators of histone H3 K9 methylation. PLoS Genet 5:1–14

    Article  Google Scholar 

  • Postepska-Igielska A, Krunic D, Greulich-Bode K, Boukamp P, Grummt I (2013) The chromatin remodeling complex NoRC safeguards genomic stability by heterochromatin formation at telomeres and centromeres. EMBO Rep, 14:704–710

    Article  CAS  Google Scholar 

  • Rubbi CP, Milner J (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 22:6068–6077

    Article  PubMed  CAS  Google Scholar 

  • Russell J, Zomerdijk JC (2005) RNA-polymerase-I-directed rDNA transcription, life and works. Trends Biochem Sci 30:87–96

    Article  PubMed  CAS  Google Scholar 

  • Russell J, Zomerdijk JC (2006) The RNA polymerase I transcription machinery. Biochem Soc Symp 73:203–216

    PubMed  CAS  Google Scholar 

  • Santoro R, Grummt I (2005) Epigenetic mechanism of rRNA gene silencing: temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation. Mol Cell Biol 25:2539–2546

    Article  PubMed  CAS  Google Scholar 

  • Santoro R, Li J, Grummt I (2002) The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat Genet 32:393–396

    Article  PubMed  CAS  Google Scholar 

  • Scheer U, Hock R (1999) Structure and function of the nucleolus. Curr Opin Cell Biol 11:385–390

    Article  PubMed  CAS  Google Scholar 

  • Scheer U, Xia B, Merkert H, Weisenberger D (1997) Looking at Christmas trees in the nucleolus. Chromosoma 105:470–480

    Google Scholar 

  • Scherl A, Couté Y, Déon Callé A, Kindbeiter K, Sanchez JC, Greco A, Hochstrasser D, Diaz JJ (2002) Functional proteomic analysis of human nucleolus. Mol Biol Cell 13:4100–4109

    Article  PubMed  CAS  Google Scholar 

  • Schreiber M, Baumann B, Cotten M, Angel P, Wagner ER (1995) Fos is an essential component of the mammalian UV response. EMBO J 14:5338–5349

    PubMed  CAS  Google Scholar 

  • Sherr CJ, Weber JD (2000) The ARF/p53 pathway. Curr Opin Genet Dev 10:94–99

    Article  PubMed  CAS  Google Scholar 

  • Strohner R, Nemeth A, Jansa P, Hofmann-Rohrer U, Santoro R, Längst G, Grummt I (2001) NoRC—a novel member of mammalian ISWI chromatin remodeling machines. EMBO J 20:4892–4900

    Article  PubMed  CAS  Google Scholar 

  • Ting DT, Lipson D, Suchismita P, Brannigan BW, Akhavanfard S, Coffman EJ, Contino G, Deshpande V, Iafrate AJ, Letovsky S, Rivera MN, Berdeesy N, Maheswaran S, Haber D (2011) Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331:593–596

    Article  PubMed  CAS  Google Scholar 

  • Tsai YC, Greco TM, Boonmee A, Miteva Y, Cristea IM (2012) Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Mol Cell Proteomics 11:60–76

    Article  PubMed  CAS  Google Scholar 

  • Vakrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober E (2008) Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 102:703–710

    Article  Google Scholar 

  • Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D (2007) SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450:440–444

    Article  PubMed  CAS  Google Scholar 

  • Yuan X, Zhou Y, Casanova E, Chai M, Kiss E, Gröne HJ, Schütz G, Grummt I (2005) Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest and p53-mediated apoptosis. Mol Cell 19:77–89

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Wolf G, Bhat K, Jin A, Allio T, Burkhart W, Xiong Y (2003) Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23:8902–8912

    Article  PubMed  CAS  Google Scholar 

  • Zhou Y, Santoro R, Grummt I (2002) The chromatin remodeling complex NoRC targets HDAC1 to the ribosomal gene promoter and represses RNA polymerase I transcription. EMBO J 21:4632–4640

    Article  PubMed  CAS  Google Scholar 

  • Zomerdijk JC, Beckmann H, Comai L, Tjian R (1994) Assembly of transcriptionally active RNA polymerase I initiation factor SL1 from recombinant subunits. Science 266:2015–2018

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany

    Ingrid Grummt

Authors
  1. Ingrid Grummt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ingrid Grummt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grummt, I. The nucleolus—guardian of cellular homeostasis and genome integrity. Chromosoma 122, 487–497 (2013). https://doi.org/10.1007/s00412-013-0430-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-013-0430-0

Keywords

Search

Navigation