Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

Oncogene volume 26, pages 5505–5520 (2007)Cite this article

Abstract

Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I–IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Agricola E, Verdone L, Di Mauro E, Caserta M . (2006). H4 acetylation does not replace H3 acetylation in chromatin remodelling and transcription activation of Adr1-dependent genes. Mol Microbiol 62: 1433–1446.

    CAS  PubMed  Google Scholar 

  • Allfrey VG, Faulkner R, Mirsky AE . (1964). Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA 51: 786–794.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Annunziato AT, Hansen JC . (2000). Role of histone acetylation in the assembly and modulation of chromatin structures. Gene Exp 9: 37–61.

    CAS  Google Scholar 

  • Ashraf N, Zino S, Macintyre A, Kingsmore D, Payne AP, George WD et al. (2006). Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 95: 1056–1061.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bae NS, Swanson MJ, Vassilev A, Howard BH . (2004). Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. J Biochem (Tokyo) 135: 695–700.

    CAS  Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444: 337–342.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Belyaev ND, Houben A, Baranczewski P, Schubert I . (1997). Histone H4 acetylation in plant heterochromatin is altered during the cell cycle. Chromosoma 106: 193–197.

    CAS  PubMed  Google Scholar 

  • Bell SD, Botting CH, Wardleworth BN, Jackson SP, White MF . (2002). The interaction of Alba, a conserved archaeal chromatin protein, with Sir2 and its regulation by acetylation. Science 296: 148–151.

    CAS  PubMed  Google Scholar 

  • Benson LJ, Gu Y, Yakovleva T, Tong K, Barrows C, Strack CL et al. (2006). Modifications of H3 and H4 during chromatin replication, nucleosome assembly, and histone exchange. J Biol Chem 281: 9287–9296.

    CAS  PubMed  Google Scholar 

  • Bernander R . (2003). The archaeal cell cycle: current issues. Mol Microbiol 48: 599–604.

    CAS  PubMed  Google Scholar 

  • Bird AW, Yu DY, Pray-Grant MG, Qiu Q, Harmon KE, Megee PC et al. (2002). Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419: 411–415.

    CAS  PubMed  Google Scholar 

  • Blander G, Guarente L . (2004). The Sir2 family of protein deacetylases. Annu Rev Biochem 73: 417–435.

    CAS  PubMed  Google Scholar 

  • Bordone L, Guarente L . (2005). Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6: 298–305.

    CAS  PubMed  Google Scholar 

  • Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND et al. (2005). SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem 280: 10264–10276.

    CAS  PubMed  Google Scholar 

  • Braunstein M, Rose AB, Holmes SG, Allis CD, Broach JR . (1993). Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev 7: 592–604.

    CAS  PubMed  Google Scholar 

  • Braunstein M, Sobel RE, Allis CD, Turner BM, Broach JR . (1996). Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol Cell Biol 16: 4349–4356.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015.

    CAS  PubMed  Google Scholar 

  • Calestagne-Morelli A, Ausió J . (2006). Long-range histone acetylation: biological significance, structural implications, and mechanisms. Biochem Cell Biol 84: 518–527.

    CAS  PubMed  Google Scholar 

  • Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P et al. (2002). Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298: 1039–1043.

    CAS  PubMed  Google Scholar 

  • Carmen AA, Milne L, Grunstein M . (2002). Acetylation of the yeast histone H4 N terminus regulates its binding to heterochromatin protein SIR3. J Biol Chem 277: 4778–4781.

    CAS  PubMed  Google Scholar 

  • Celic I, Masumoto H, Griffith WP, Meluh P, Cotter RJ, Boeke JD et al. (2006). The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation. Curr Biol 16: 1280–1289.

    CAS  PubMed  Google Scholar 

  • Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB . (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123: 437–448.

    CAS  PubMed  Google Scholar 

  • Chiani F, Di Felice F, Camilloni G . (2006). SIR2 modifies histone H4-K16 acetylation and affects superhelicity in the ARS region of plasmid chromatin in Saccharomyces cerevisiae. Nucleic Acids Res 34: 5426–5437.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S et al. (2005). Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2: 67–76.

    CAS  PubMed  Google Scholar 

  • Clapier CR, Nightingale KP, Becker PB . 2002)). A critical epitope for substrate recognition by the nucleosome remodeling ATPase ISWI. Nucleic Acids Res 30: 649–655.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clarke DJ, O'Neill LP, Turner BM . (1993). Selective use of H4 acetylation sites in the yeast Saccharomyces cerevisiae. Biochem J 294: 557–561.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B et al. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305: 390–392.

    CAS  PubMed  Google Scholar 

  • Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V . (2002). Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111: 185–196.

    CAS  PubMed  Google Scholar 

  • Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ . (2007). SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J Cell Physiol 210: 161–166.

    CAS  PubMed  Google Scholar 

  • De la Cruz X, Lois S, Sanchez-Molina S, Martinez-Balbas MA . (2005). Do protein motifs read the histone code? Bioessays 27: 164–175.

    CAS  PubMed  Google Scholar 

  • Dion MF, Altschuler SJ, Wu LF, Rando OJ . (2005). Genomic characterization reveals a simple histone H4 acetylation code. Proc Natl Acad Sci USA 102: 5501–5506.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dorigo B, Schalch T, Bystricky K, Richmond TJ . (2003). Chromatin fiber folding: requirement for the histone H4 N-terminal tail. J Mol Biol 327: 85–96.

    CAS  PubMed  Google Scholar 

  • Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J et al. (2005). Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121: 873–885.

    CAS  PubMed  Google Scholar 

  • Downs JA, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, Bouchard N et al. (2004). Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol Cell 16: 979–990.

    CAS  PubMed  Google Scholar 

  • Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA . (2003). Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol 23: 3173–3185.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Durrin LK, Mann RK, Kayne PS, Grunstein M . (1991). Yeast histone H4 N-terminal sequence is required for promoter activation in vivo. Cell 65: 1023–1031.

    CAS  PubMed  Google Scholar 

  • Ekwall K . (2005). Genome-wide analysis of HDAC function. Trends Genet 21: 608–615.

    CAS  PubMed  Google Scholar 

  • Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K et al. (2005). Sir2 blocks extreme life-span extension. Cell 123: 655–667.

    CAS  PubMed  Google Scholar 

  • Fisher-Adams G, Grunstein M . (1995). Yeast histone H4 and H3 N-termini have different effects on the chromatin structure of the GAL1 promoter. EMBO J 14: 1468–1477.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Feinberg AP, Vogelstein B . (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301: 89–92.

    CAS  PubMed  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391–400.

    CAS  PubMed  Google Scholar 

  • Frye RA . (1999). Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 260: 273–279.

    CAS  PubMed  Google Scholar 

  • Frye RA . (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273: 793–798.

    CAS  PubMed  Google Scholar 

  • Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y et al. (2003). Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12: 51–62.

    CAS  PubMed  Google Scholar 

  • Furuyama T, Banerjee R, Breen TR, Harte PJ . (2004). SIR2 is required for polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr Biol 14: 1812–1821.

    CAS  PubMed  Google Scholar 

  • Gartenberg MR . (2000). The Sir proteins of Saccharomyces cerevisiae: mediators of transcriptional silencing and much more. Curr Opin Microbiol 3: 132–137.

    CAS  PubMed  Google Scholar 

  • Giannakou ME, Partridge L . (2004). The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 14: 408–412.

    CAS  PubMed  Google Scholar 

  • Glowczewski L, Waterborg JH, Berman JG . (2004). Yeast chromatin assembly complex 1 protein excludes nonacetylatable forms of histone H4 from chromatin and the nucleus. Mol Cell Biol 24: 10180–10192.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grunstein M . (1997). Histone acetylation in chromatin structure and transcription. Nature 389: 349–352.

    CAS  PubMed  Google Scholar 

  • Guarente L . (1999). Diverse and dynamic functions of the Sir silencing complex. Nat Genet 23: 281–285.

    CAS  PubMed  Google Scholar 

  • Guarente L . (2005). Calorie restriction and SIR2 genes – towards a mechanism. Mech Ageing Dev 126: 923–928.

    CAS  PubMed  Google Scholar 

  • Gupta A, Sharma GG, Young CS, Agarwal M, Smith ER, Paull TT et al. (2005). Involvement of human MOF in ATM function. Mol Cell Biol 25: 5292–5305.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haigis MC, Guarente LP . (2006). Mammalian sirtuins – emerging roles in physiology, aging, and calorie restriction. Genes Dev 20: 2913–2921.

    CAS  PubMed  Google Scholar 

  • Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ et al. (2006b). SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126: 941–954.

    CAS  PubMed  Google Scholar 

  • Halme A, Bumgarner S, Styles C, Fink GR . (2004). Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast. Cell 116: 405–415.

    CAS  PubMed  Google Scholar 

  • Hassan AH, Neely KE, Workman JL . (2001). Histone acetyltransferase complexes stabilize SWI/SNF binding to promoter nucleosomes. Cell 104: 817–827.

    CAS  PubMed  Google Scholar 

  • Hecht A, Laroche T, Strahl-Bolsinger S, Gasser SM, Grunstein M . (1995). Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80: 583–592.

    CAS  PubMed  Google Scholar 

  • Henikoff S . (2005). Histone modifications: combinatorial complexity or cumulative simplicity? Proc Natl Acad Sci USA 102: 5308–5309.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi JC . (1997). mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J 16: 2054–2060.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H et al. (2003). Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun 309: 558–566.

    CAS  PubMed  Google Scholar 

  • Huang S, Litt M, Felsenfeld G . (2005). Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications. Genes Dev 19: 1885–1893.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Imai S, Armstrong CM, Kaeberlein M, Guarente L . (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800.

    CAS  PubMed  Google Scholar 

  • Jasencakova Z, Meister A, Walter J, Turner BM, Schubert I . (2000). Histone H4 acetylation of euchromatin and heterochromatin is cell cycle dependent and correlated with replication rather than with transcription. Plant Cell 12: 2087–2100.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jazayeri A, McAinsh AD, Jackson SP . (2004). Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair. Proc Natl Acad Sci USA 101: 1644–1649.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jenuwein T, Allis CD . (2001). Translating the histone code. Science 293: 1074–1080.

    CAS  PubMed  Google Scholar 

  • Jeppesen P, Turner BM . (1993). The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74: 281–289.

    CAS  PubMed  Google Scholar 

  • Johnson LM, Kayne PS, Kahn ES, Grunstein M . (1990). Genetic evidence for an interaction between SIR3 and histone H4 in the repression of the silent mating loci in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 87: 6286–6290.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaeberlein M, Powers III RW, Steffen KK, Westman EA, Hu D, Dang N et al. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310: 1193–1196.

    CAS  PubMed  Google Scholar 

  • Kayne PS, Kim UJ, Han M, Mullen JR, Yoshizaki F, Grunstein M . (1988). Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast. Cell 55: 27–39.

    CAS  PubMed  Google Scholar 

  • Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabb DS, Murthy M et al. (1997). Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89: 381–391.

    CAS  PubMed  Google Scholar 

  • Kimura A, Umehara T, Horikoshi M . (2002). Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nat Genet 32: 370–377.

    PubMed  Google Scholar 

  • Kouzarides T . (2000). Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19: 1176–1179.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isshiki K et al. (2007). SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. J Biol Chem 282: 151–158.

    CAS  PubMed  Google Scholar 

  • Kurdistani SK, Grunstein M . (2003). Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol 4: 276–284.

    CAS  PubMed  Google Scholar 

  • Kurdistani SK, Tavazoie S, Grunstein M . (2004). Mapping global histone acetylation patterns to gene expression. Cell 117: 721–733.

    CAS  PubMed  Google Scholar 

  • Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG . (2005). Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol 12: 624–625.

    CAS  PubMed  Google Scholar 

  • Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D . (2002). Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16: 2893–28905.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A et al. (2005). Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci USA 102: 1859–1864.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ladurner AG, Inouye C, Jain R, Tjian R . (2003). Bromodomains mediate an acetyl-histone encoded antisilencing function at heterochromatin boundaries. Mol Cell 11: 365–376.

    CAS  PubMed  Google Scholar 

  • Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L et al. (2000a). The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA 97: 5807–5811.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Landry J, Slama JT, Sternglanz R . (2000b). Role of NAD(+) in the deacetylase activity of the SIR2-like proteins. Biochem Biophys Res Commun 278: 685–690.

    CAS  PubMed  Google Scholar 

  • Lavender JS, Birley AJ, Palmer MJ, Kuroda MI, Turner BM . (1994). Histone H4 acetylated at lysine 16 and proteins of the Drosophila dosage compensation pathway co-localize on the male X chromosome through mitosis. Chromosome Res 2: 398–404.

    CAS  PubMed  Google Scholar 

  • Leipe DD, Landsman D . (1997). Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily. Nucleic Acids Res 25: 3693–3697.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liou GG, Tanny JC, Kruger RG, Walz T, Moazed D . (2005). Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation. Cell 121: 515–527.

    CAS  PubMed  Google Scholar 

  • Longo VD, Kennedy BK . (2006). Sirtuins in aging and age-related disease. Cell 126: 257–268.

    CAS  PubMed  Google Scholar 

  • Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137–148.

    CAS  PubMed  Google Scholar 

  • Ma XJ, Wu J, Altheim BA, Schultz MC, Grunstein M . (1998). Deposition-related sites K5/K12 in histone H4 are not required for nucleosome deposition in yeast. Proc Natl Acad Sci USA 95: 6693–6698.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maas NL, Miller KM, DeFazio LG, Toczyski DP . (2006). Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4. Mol Cell 23: 109–119.

    CAS  PubMed  Google Scholar 

  • Margueron R, Trojer P, Reinberg D . (2005). The key to development: interpreting the histone code? Curr Opin Genet Dev 15: 163–176.

    CAS  PubMed  Google Scholar 

  • Marmorstein R . (2004). Structure and chemistry of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochem Soc Trans 32: 904–909.

    CAS  PubMed  Google Scholar 

  • Megee PC, Morgan BA, Mittman BA, Smith MM . (1990). Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. Science 247: 841–845.

    CAS  PubMed  Google Scholar 

  • Megee PC, Morgan BA, Smith MM . (1995). Histone H4 and the maintenance of genome integrity. Genes Dev 9: 1716–1727.

    CAS  PubMed  Google Scholar 

  • Mellone BG, Ball L, Suka N, Grunstein MR, Partridge JF, Allshire RC . (2003). Centromere silencing and function in fission yeast is governed by the amino terminus of histone H3. Curr Biol 13: 1748–1757.

    CAS  PubMed  Google Scholar 

  • Meyer-Ficca ML, Meyer RG, Jacobson EL, Jacobson MK . (2005). Poly(ADP-ribose) polymerases: managing genome stability. Int J Biochem Cell Biol 37: 920–926.

    CAS  PubMed  Google Scholar 

  • Millar CB, Kurdistani SK, Grunstein M . (2006). Acetylation of yeast histone H4 lysine 16: a switch for protein interactions in heterochromatin and euchromatin. Cold Spring Harb Symp Quant Biol 69: 193–200.

    Google Scholar 

  • Min J, Landry J, Sternglanz R, Xu RM . (2001). Crystal structure of a SIR2 homolog-NAD complex. Cell 105: 269–279.

    CAS  PubMed  Google Scholar 

  • Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L et al. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124: 315–329.

    CAS  PubMed  Google Scholar 

  • Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W et al. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551–563.

    CAS  PubMed  Google Scholar 

  • Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C et al. (2005). Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2: 105–117.

    CAS  PubMed  Google Scholar 

  • Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B et al. (2002). Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111: 197–208.

    CAS  PubMed  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nathan D, Ingvarsdottir K, Sterner DE, Bylebyl GR, Dokmanovic M, Dorsey JA et al. (2006). Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev 20: 966–976.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nightingale KP, O'Neill LP, Turner BM . (2006). Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr Opin Genet Dev 16: 125–136.

    CAS  PubMed  Google Scholar 

  • North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . (2003). The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11: 437–444.

    CAS  PubMed  Google Scholar 

  • O'Neill LP, VerMilyea MD, Turner BM . (2006). Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nat Genet 38: 835–841.

    CAS  PubMed  Google Scholar 

  • Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP . (2002). SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci USA 99: 13653–13658.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P et al. (2000). The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J 19: 6141–6149.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park EC, Szostak JW . (1990). Point mutations in the yeast histone H4 gene prevent silencing of the silent mating type locus HML. Mol Cell Biol 10: 4932–4934.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perrod S, Cockell MM, Laroche T, Renauld H, Ducrest AL, Bonnard C et al. (2001). A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar and telomeric silencing in yeast. EMBO J 20: 197–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R et al. (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429: 771–776.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pogribny IP, Tryndyak VP, Muskhelishvili L, Rusyn I, Ross SA . (2007). Methyl deficiency, alterations in global histone modifications, and carcinogenesis. J Nutr 137: 216S–222S.

    CAS  PubMed  Google Scholar 

  • Polevoda B, Sherman F . (2002). The diversity of acetylated proteins. Genome Biol 3: reviews0006.

    PubMed  PubMed Central  Google Scholar 

  • Polo SE, Almouzni G . (2006). Chromatin assembly: a basic recipe with various flavours. Curr Opin Genet Dev 16: 104–111.

    CAS  PubMed  Google Scholar 

  • Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN et al. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2: e40.

    PubMed  PubMed Central  Google Scholar 

  • Rea S, Xouri G, Akhtar A . (2007). Male absent on the first (MOF): from flies to humans. Oncogene 26: 5385–5394.

    CAS  PubMed  Google Scholar 

  • Robyr D, Suka Y, Xenarios I, Kurdistani SK, Wang A, Suka N et al. (2002). Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109: 437–446.

    CAS  PubMed  Google Scholar 

  • Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P . (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118.

    CAS  PubMed  Google Scholar 

  • Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V et al. (2003). Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol 38: 1065–1070.

    CAS  PubMed  Google Scholar 

  • Rosenberg MI, Parkhurst SM . (2002). Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell 109: 447–458.

    CAS  PubMed  Google Scholar 

  • Roth SY, Denu JM, Allis CD . (2001). Histone acetyltransferases. Annu Rev Biochem 70: 81–120.

    CAS  PubMed  Google Scholar 

  • Rougeulle C, Chaumeil J, Sarma K, Allis CD, Reinberg D, Avner P et al. (2004). Differential histone H3 Lys-9 and Lys-27 methylation profiles on the X chromosome. Mol Cell Biol 24: 5475–5484.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sakurada K, Ohta T, Fujishiro K, Hasegawa M, Aisaka K . (1996). Acetylpolyamine amidohydrolase from mycoplana ramosa: gene cloning and characterization of the metal-substituted enzyme. J Bacteriol 178: 5781–5786.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sandmeier JJ, Celic I, Boeke JD, Smith JS . (2002). Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway. Genetics 160: 877–889.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sarma K, Reinberg D . (2005). Histone variants meet their match. Nat Rev Mol Cell Biol 6: 139–149.

    CAS  PubMed  Google Scholar 

  • Sauve AA, Schramm VL . (2003). Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 42: 9249–9256.

    CAS  PubMed  Google Scholar 

  • Sauve AA, Wolberger C, Schramm VL, Boeke JD . (2006). The biochemistry of sirtuins. Annu Rev Biochem 75: 435–465.

    CAS  PubMed  Google Scholar 

  • Scher M, Vaquero A, Reinberg D . (2007). SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev 21: 920–928.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E . (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci USA 103: 10224–10229.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schwer B, North BJ, Frye RA, Ott M, Verdin E . (2002). The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 158: 647–657.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S et al. (2003). Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression. J Biol Chem 278: 43041–43050.

    CAS  PubMed  Google Scholar 

  • Shankaranarayana GD, Motamedi MR, Moazed D, Grewal SI . (2003). Sir2 regulates histone H3 lysine 9 methylation and heterochromatin assembly in fission yeast. Curr Biol 13: 1240–1246.

    CAS  PubMed  Google Scholar 

  • Shi T, Wang F, Stieren E, Tong Q . (2005). SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280: 13560–13567.

    CAS  PubMed  Google Scholar 

  • Shia WJ, Li B, Workman JL . (2006). SAS-mediated acetylation of histone H4 Lys 16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae. Genes Dev 20: 2507–2512.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL . (2006). Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311: 844–847.

    CAS  PubMed  Google Scholar 

  • Sinclair DA, Guarente L . (1997). Extrachromosomal rDNA circles – a cause of aging in yeast. Cell 91: 1033–1042.

    CAS  PubMed  Google Scholar 

  • Smith CM, Gafken PR, Zhang Z, Gottschling DE, Smith JB, Smith DL . (2003). Mass spectrometric quantification of acetylation at specific lysines within the amino-terminal tail of histone H4. Anal Biochem 316: 23–33.

    CAS  PubMed  Google Scholar 

  • Smith ER, Cayrou C, Huang R, Lane WS, Cote J, Lucchesi JC . (2005). A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol Cell Biol 25: 9175–9188.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sobel RE, Cook RG, Perry CA, Annunziato AT, Allis CD . (1995). Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. Proc Natl Acad Sci USA 92: 1237–1241.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Starai VJ, Celic I, Cole RN, Boeke JD, Escalante-Semerena JC . (2002). Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 298: 2390–2392.

    CAS  PubMed  Google Scholar 

  • Sterner DE, Berger SL . (2000). Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64: 435–459.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suka N, Suka Y, Carmen AA, Wu J, Grunstein M . (2001). Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin. Mol Cell 8: 473–479.

    CAS  PubMed  Google Scholar 

  • Suka N, Luo K, Grunstein M . (2002). Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nat Genet 32: 378–383.

    CAS  PubMed  Google Scholar 

  • Taipale M, Rea S, Richter K, Vilar A, Lichter P, Imhof A et al. (2005). hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol Cell Biol 25: 6798–6810.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Takata T, Ishikawa F . (2003). Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Biochem Biophys Res Commun 301: 250–257.

    CAS  PubMed  Google Scholar 

  • Tanny JC, Dowd GJ, Huang J, Hilz H, Moazed D . (1999). An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99: 735–745.

    CAS  PubMed  Google Scholar 

  • Tissenbaum HA, Guarente L . (2001). Increased dosage of a Sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410: 227–230.

    CAS  PubMed  Google Scholar 

  • Tsang AW, Escalante-Semerena JC . (1998). CobB, a new member of the Sir2 family of eucaryotic regulatory proteins, is required to compensate for the lack of nicotinate mononucleotide: 5,6-dimethylbenzimidazole phosphoribosyltransferase activity in cobT mutants during cobalamin biosynthesis in Salmonella typhimurium LT2. J Biol Chem 273: 31788–31794.

    CAS  PubMed  Google Scholar 

  • Tsuchiya M, Dang N, Kerr EO, Hu D, Steffen KK, Oakes JA et al. (2006). Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell 5: 505–514.

    CAS  PubMed  Google Scholar 

  • Turner BM, Birley AJ, Lavender J . (1992). Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell 69: 375–384.

    CAS  PubMed  Google Scholar 

  • Turner BM, O'Neill LP, Allan IM . (1989). Histone H4 acetylation in human cells. Frequency of acetylation at different sites defined by immunolabeling with site-specific antibodies. FEBS Lett 253: 141–145.

    CAS  PubMed  Google Scholar 

  • Turner BM . (2000). Histone acetylation and an epigenetic code. Bioessays 22: 836–845.

    CAS  PubMed  Google Scholar 

  • van Leeuwen F, Gottschling DE . (2002). Genome-wide histone modifications: gaining specificity by preventing promiscuity. Curr Opin Cell Biol 14: 756–762.

    CAS  PubMed  Google Scholar 

  • Vaquero A, Loyola A, Reinberg D . (2003). The constantly changing face of chromatin. Sci Aging Knowledge Environ 2003: RE4.

    PubMed  Google Scholar 

  • Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D . (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16: 93–105.

    CAS  PubMed  Google Scholar 

  • Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW et al. (2006a). SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 20: 1256–1261.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vaquero A, Scher M, Reinberg D . (2006b). Biochemistry Of Multiprotein HDAC Complexes. In: Verdin E (ed). Histone Deacetylases: Transcription Regulation and Other Cellular Functions. Humana Press: NJ (USA), pp 23–60.

    Google Scholar 

  • Vaquero A, Scher M, Erdjument Bromage H, Tempst P, Serrano L, Reinberg D . Sirt1 regulates the histone methylation activity of Suv39h1 during facultative heterochromatin formation. Submitted.

  • Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149–159.

    CAS  PubMed  Google Scholar 

  • Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y et al. (2006). Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 8: 1025–1031.

    CAS  PubMed  Google Scholar 

  • Wilson JM, Le VQ, Zimmerman C, Marmorstein R, Pillus L . (2006). Nuclear export modulates the cytoplasmic Sir2 homologue Hst2. EMBO Rep 7: 1247–1251.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J, Pierce M, Gailus-Durner V, Wagner M, Winter E, Vershon AK . (1999). Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae. EMBO J 18: 6448–6454.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu F, Zhang K, Grunstein M . (2005). Acetylation in histone H3 globular domain regulates gene expression in yeast. Cell 121: 375–385.

    CAS  PubMed  Google Scholar 

  • Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA et al. (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23: 2369–2380.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Teng Y, Liu H, Reed SH, Waters R . (2005). UV irradiation stimulates histone acetylation and chromatin remodeling at a repressed yeast locus. Proc Natl Acad Sci USA 102: 8650–8655.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Roberts DN, Cairns BR . (2005). Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 123: 219–231.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Grummt I . (2005). The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr Biol 15: 1434–1438.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs Hannah Klein and Lynne Vales for discussion and Dr Lynne Vales for reading the manuscript. This work was supported by NIH grants GM64844 (DR) and GM28220 (RS), and by the HHMI (DR).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Howard Hughes Medical Institute, NYU School of Medicine-Smilow Research Center, New York, NY, USA

    A Vaquero & D Reinberg

  2. ICREA and IBMB-CSIC, Parc Científic de Barcelona, Barcelona, Spain

    A Vaquero

  3. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA

    R Sternglanz

Authors
  1. A Vaquero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Sternglanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Reinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Reinberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaquero, A., Sternglanz, R. & Reinberg, D. NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 26, 5505–5520 (2007). https://doi.org/10.1038/sj.onc.1210617

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210617

Keywords

This article is cited by

Search

Advanced search

Quick links