SIRT1 negatively regulates rRNA expression (Homo sapiens)

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3, 10, 121079, 107, 10cytosolnucleoplasm2'-O-acetyl-ADP-riboseTAF1A HIST1H4 AdoHcyH3F3A HIST2H3A SL1TAF1D NAD+TBP 5.8S rRNA Chromatin withacetylated H3RRP8 RRP8 HIST1H4 Acetylated SL1NAMSUV39H1 28S rRNA AdoMet5S rRNA Me2K-10-H3F3A 2xAcK-H3F3A RRP8:5S RNA, rRNAHIST1H4 HIST1H4 TBP TAF1C TAF1D RRP82xAcK-HIST1H3A SUV39H1ChromatinMe2K-10-HIST2H3A TAF1A Me2K10-HIST1H3A Chromatin (H3K9me2)Me2K10-HIST1H3A Ac-TAF1B TAF1C 2xAcK-HIST2H3A SIRT1 Me2K-10-H3F3A eNoSCSIRT1HIST1H3A 5S RNA, 5.8S rRNA,28S rRNATAF1B Me2K-10-HIST2H3A 77101, 2, 4, 5, 8116


Expression of rRNA genes is coupled to the overall metabolism of the cell by the NAD-dependent histone deacetylase SIRT1, a component of the Energy-dependent Nucleolar Silencing Complex (eNoSC) (Murayama et al. 2008, reviewed in Salminen and Kaarniranta 2009, Grummt and Voit 2010). eNoSC comprises Nucleomethylin (NML), SIRT1, and the histone methylase SUV39H1 (Murayama et al. 2008). Deacetylation and methylation of histone H3 in the chromatin of a rRNA gene by eNoSC causes reduced expression of the gene. When glucose is low, NAD is high (NADH is low), activity of SIRT1 is high, and activity of rRNA genes is reduced. It is hypothesized that eNoSC forms on a nucleosome containing dimethylated lysine-9 on histone H3 (H3K9me2) and then eNoSC deacetylates and dimethylates the adjacent nucleosome, thus catalyzing spreading of H3K9me2 throughout the gene. Source:Reactome.

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  1. Grummt I, Voit R.; ''Linking rDNA transcription to the cellular energy supply.''; PubMed Europe PMC Scholia
  2. Gorski JJ, Pathak S, Panov K, Kasciukovic T, Panova T, Russell J, Zomerdijk JC.; ''A novel TBP-associated factor of SL1 functions in RNA polymerase I transcription.''; PubMed Europe PMC Scholia
  3. Pijnappel WP, Kolkman A, Baltissen MP, Heck AJ, Timmers HM.; ''Quantitative mass spectrometry of TATA binding protein-containing complexes and subunit phosphorylations during the cell cycle.''; PubMed Europe PMC Scholia
  4. Yang L, Song T, Chen L, Kabra N, Zheng H, Koomen J, Seto E, Chen J.; ''Regulation of SirT1-nucleomethylin binding by rRNA coordinates ribosome biogenesis with nutrient availability.''; PubMed Europe PMC Scholia
  5. Comai L, Tanese N, Tjian R.; ''The TATA-binding protein and associated factors are integral components of the RNA polymerase I transcription factor, SL1.''; PubMed Europe PMC Scholia
  6. Muth V, Nadaud S, Grummt I, Voit R.; ''Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription.''; PubMed Europe PMC Scholia
  7. Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMed Europe PMC Scholia
  8. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.''; PubMed Europe PMC Scholia
  9. Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J.; ''Epigenetic control of rDNA loci in response to intracellular energy status.''; PubMed Europe PMC Scholia
  10. Salminen A, Kaarniranta K.; ''SIRT1 regulates the ribosomal DNA locus: epigenetic candles twinkle longevity in the Christmas tree.''; PubMed Europe PMC Scholia
  11. Comai L, Zomerdijk JC, Beckmann H, Zhou S, Admon A, Tjian R.; ''Reconstitution of transcription factor SL1: exclusive binding of TBP by SL1 or TFIID subunits.''; PubMed Europe PMC Scholia
  12. Bell SP, Pikaard CS, Reeder RH, Tjian R.; ''Molecular mechanisms governing species-specific transcription of ribosomal RNA.''; PubMed Europe PMC Scholia


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External references


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NameTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseMetaboliteCHEBI:76279 (ChEBI)
28S rRNA ProteinM11167 (EMBL)
2xAcK-H3F3A ProteinP84243 (Uniprot-TrEMBL)
2xAcK-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
2xAcK-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
5.8S rRNA ProteinJ01866 (EMBL)
5S RNA, 5.8S rRNA, 28S rRNAR-HSA-5096484 (Reactome)
5S rRNA ProteinV00589 (EMBL)
Ac-TAF1B ProteinQ53T94 (Uniprot-TrEMBL)
Acetylated SL1ComplexR-HSA-73693 (Reactome)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
Chromatin (H3K9me2)ComplexR-HSA-3211683 (Reactome)
Chromatin with acetylated H3ComplexR-HSA-3211727 (Reactome)
ChromatinComplexR-HSA-3211736 (Reactome)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me2K-10-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me2K-10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me2K10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
RRP8 ProteinO43159 (Uniprot-TrEMBL)
RRP8:5S RNA, rRNAComplexR-HSA-5096496 (Reactome)
RRP8ProteinO43159 (Uniprot-TrEMBL)
SIRT1 ProteinQ96EB6 (Uniprot-TrEMBL)
SIRT1ProteinQ96EB6 (Uniprot-TrEMBL)
SL1ComplexR-HSA-73692 (Reactome)
SUV39H1 ProteinO43463 (Uniprot-TrEMBL)
SUV39H1ProteinO43463 (Uniprot-TrEMBL)
TAF1A ProteinQ15573 (Uniprot-TrEMBL)
TAF1B ProteinQ53T94 (Uniprot-TrEMBL)
TAF1C ProteinQ15572 (Uniprot-TrEMBL)
TAF1D ProteinQ9H5J8 (Uniprot-TrEMBL)
TBP ProteinP20226 (Uniprot-TrEMBL)
eNoSCComplexR-HSA-427510 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseArrowR-HSA-427514 (Reactome)
2'-O-acetyl-ADP-riboseArrowR-HSA-5211239 (Reactome)
5S RNA, 5.8S rRNA, 28S rRNAR-HSA-5096488 (Reactome)
5S RNA, 5.8S rRNA, 28S rRNATBarR-HSA-427528 (Reactome)
Acetylated SL1R-HSA-5211239 (Reactome)
AdoHcyArrowR-HSA-427527 (Reactome)
AdoMetR-HSA-427527 (Reactome)
Chromatin (H3K9me2)ArrowR-HSA-427527 (Reactome)
Chromatin (H3K9me2)R-HSA-427528 (Reactome)
Chromatin with acetylated H3R-HSA-427514 (Reactome)
ChromatinArrowR-HSA-427514 (Reactome)
ChromatinR-HSA-427527 (Reactome)
NAD+R-HSA-427514 (Reactome)
NAD+R-HSA-5211239 (Reactome)
NAMArrowR-HSA-427514 (Reactome)
NAMArrowR-HSA-5211239 (Reactome)
R-HSA-427514 (Reactome) The Sirtuin-1 (SIRT1) component of eNoSC deacetylates histone H3 at lysine-9 (Vaquero et al. 2004, Murayama et al. 2008). The reaction uses nicotinamide adenine dinucleotide (NAD) as the acceptor of the acetyl group and generates nicotinamide and 1-O-acetyl-ADP-ribose as products (Vaquero et al. 2004). The use of NAD links the reaction to the overall energy balance of the cell. Cells exposed to high glucose have a greater NADH:NAD ratio and therefore lower activity of eNoSC (Murayama et al. 2008). Low glucose produces higher NAD and higher activity of eNoSC.
R-HSA-427527 (Reactome) The SUV39H1 component of eNoSC dimethylates histone H3 at lysine-9 (Murayama et al. 2008). The reaction depends on the prior deacetylation reaction catalyzed by the SIRT1 component of eNoSC. Histone H3 dimethylated at lysine-9 inhibits expression of rRNA genes.
R-HSA-427528 (Reactome) RRP8 (Nucleomethylin, NML), SIRT1, and SUV39H1 form the energy-dependent Nucleolar Silencing Complex (eNoSC) at inactive rRNA genes (Murayama et al. 2008). RRP8 is constitutively located in the nucleolus (Yang et al. 2013), binds histone H3 dimethylated at lysine-9 (Murayama et al. 2008) and appears to recruit SIRT1 from the nucleoplasm to the nucleolus (Yang et al. 2013). The eNoSC binds chromatin throughout the rRNA transcription unit. SIRT1 may deacetylate and, hence, activate SUV39H1 but this has not yet been shown at rDNA. Abrogation of any member of eNoSC interferes with binding of the other members of the complex. The eNoSC complex appears to cause spreading of heterochromatin at rDNA.
R-HSA-5096488 (Reactome) RRP8 (Nucleomethylin, NML) recruits SIRT1 to the nucleolus to form the energy-dependent Nucleolar Silencing Complex (eNoSC), which induces chromatin changes that inhibit rRNA transcription. RRP8 can bind 5S RNA (transcribed by RNA ploymerase III), 5.8S rRNA, and 28S rRNA and the bound RNA prevents RRP8 from binding SIRT1 (Yang et al. 2013). Thus the level of 5S RNA, 5.8S rRNA, and 28S rRNA in the nucleus negatively regulates the assembly of eNoSC, coupling transcriptional regulation of rRNA to epigenetic silencing of rRNA genes.
R-HSA-5211239 (Reactome) As inferred from mouse, SIRT1, an NAD+ dependent deacetylase, deacetylates the TAF1B (TAF(1)68) subunit of the SL1 complex. Deacetylation of TAF1B inhibits transcription of rRNA genes.
RRP8:5S RNA, rRNAArrowR-HSA-5096488 (Reactome)
RRP8R-HSA-427528 (Reactome)
RRP8R-HSA-5096488 (Reactome)
SIRT1R-HSA-427528 (Reactome)
SIRT1mim-catalysisR-HSA-5211239 (Reactome)
SL1ArrowR-HSA-5211239 (Reactome)
SUV39H1R-HSA-427528 (Reactome)
eNoSCArrowR-HSA-427528 (Reactome)
eNoSCmim-catalysisR-HSA-427514 (Reactome)
eNoSCmim-catalysisR-HSA-427527 (Reactome)
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