The Rtt109-Vps75 Histone Acetyltransferase Complex Acetylates Non-nucleosomal Histone H3

Acetylation of lysine 56 of histone H3 (H3-Lys-56) occurs in S phase and disappears during G2/M phase of the cell cycle. However, it is not clear how this modification is regulated during the progression of the cell cycle. We and others have shown that the histone acetyltransferase (HAT) Rtt109 is the primary HAT responsible for acetylating H3-Lys-56 in budding yeast. Here we show that Rtt109 forms a complex with Vps75 and that both recombinant Rtt109-Vps75 complexes and native complexes purified from yeast cells acetylate H3 present in H3/H4/H2A/H2B core histones but not other histones. In addition, both recombinant and native Rtt109-Vps75 HAT complexes exhibited no detectable activity toward nucleosomal H3, suggesting that H3-Lys-56 acetylation is at least in part regulated by the inability of Rtt109-Vps75 complexes to acetylate nucleosomal H3 during G2/M phase of the cell cycle. Further, Rtt109 bound mutant H3/H4 tetramers composed of histones lacking their N-terminal tail domains less efficiently than wild-type H3/H4 tetramers, and Rtt109-Vps75 complexes displayed reduced HAT activity toward these mutant H3/H4 tetramers. Thus, the N termini of H3/H4 tetramers are required for efficient acetylation of H3 by the Rtt109-Vps75 complex. Taken together, these studies provide insights into how H3-Lys-56 acetylation is regulated during the cell cycle. Acetylation of lysine 56 of histone H3 (H3-Lys-56) occurs in S phase and disappears during G2/M phase of the cell cycle. However, it is not clear how this modification is regulated during the progression of the cell cycle. We and others have shown that the histone acetyltransferase (HAT) Rtt109 is the primary HAT responsible for acetylating H3-Lys-56 in budding yeast. Here we show that Rtt109 forms a complex with Vps75 and that both recombinant Rtt109-Vps75 complexes and native complexes purified from yeast cells acetylate H3 present in H3/H4/H2A/H2B core histones but not other histones. In addition, both recombinant and native Rtt109-Vps75 HAT complexes exhibited no detectable activity toward nucleosomal H3, suggesting that H3-Lys-56 acetylation is at least in part regulated by the inability of Rtt109-Vps75 complexes to acetylate nucleosomal H3 during G2/M phase of the cell cycle. Further, Rtt109 bound mutant H3/H4 tetramers composed of histones lacking their N-terminal tail domains less efficiently than wild-type H3/H4 tetramers, and Rtt109-Vps75 complexes displayed reduced HAT activity toward these mutant H3/H4 tetramers. Thus, the N termini of H3/H4 tetramers are required for efficient acetylation of H3 by the Rtt109-Vps75 complex. Taken together, these studies provide insights into how H3-Lys-56 acetylation is regulated during the cell cycle. In eukaryotic cells, nucleosomes comprising ∼146 bp of DNA wrapped around histone octamers form the basic unit of chromatin (1van Holde K.E. Chromatin, Springer-Verlag, New York. 1989; Google Scholar, 2Luger K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Nature. 1997; 389: 251-260Crossref PubMed Scopus (6926) Google Scholar). In recent years, it has become clear that chromatin is dynamically regulated during the processes of transcription, DNA repair, and DNA replication (3Luger K. Chromosome Res. 2006; 14: 5-16Crossref PubMed Scopus (134) Google Scholar). One of the primary means of regulating chromatin structure and function is mediated by posttranslational modification of histones, including acetylation, methylation, and ubiquitination (4Strahl B.D. Allis C.D. Nature. 2000; 403: 41-45Crossref PubMed Scopus (6623) Google Scholar, 5Jenuwein T. Allis C.D. Science. 2001; 293: 1074-1080Crossref PubMed Scopus (7666) Google Scholar, 6Zhang Y. Reinberg D. Genes Dev. 2001; 15: 2343-2360Crossref PubMed Scopus (1243) Google Scholar). Histone acetylation plays an important role in transcription, DNA replication, nucleosome assembly, and DNA repair (7Roth S.Y. Allis C.D. Cell. 1996; 87: 5-8Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 8Roth S.Y. Denu J.M. Allis C.D. Annu. Rev. Biochem. 2001; 70: 81-120Crossref PubMed Scopus (1610) Google Scholar, 9Carrozza M.J. Utley R.T. Workman J.L. Cote J. Trends Genet. 2003; 19: 321-329Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar). These diverse functions are likely to be carried out by distinct histone acetyltransferases (HATs) 2The abbreviations used are: HAT, histone acetyltransferase; HDAC, histone deacetylase; TAP, tandem affinity purification; CBB, Coomassie Brilliant Blue; NAP1, nucleosome assembly protein 1; INHAT, inhibitor of acetyltransferases; GST, glutathione S-transferase. that target different lysine residues on distinct histones. Although the acetylation of N-terminal lysine residues of histones H3/H4 is well known, lysine 56 of H3 (H3-Lys-56), a lysine residue in the core domain of H3, has only more recently been found to be acetylated (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar, 11Ozdemir A. Spicuglia S. Lasonder E. Vermeulen M. Campsteijn C. Stunnenberg H.G. Logie C. J. Biol. Chem. 2005; 280: 25949-25952Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 12Xu F. Zhang K. Grunstein M. Cell. 2005; 121: 375-385Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 13Hyland E.M. Cosgrove M.S. Molina H. Wang D. Pandey A. Cottee R.J. Boeke J.D. Mol. Cell. Biol. 2005; 25: 10060-10070Crossref PubMed Scopus (190) Google Scholar, 14Zhou H. Madden B.J. Muddiman D.C. Zhang Z. Biochemistry. 2006; 45: 2852-2861Crossref PubMed Scopus (63) Google Scholar). Further, in contrast to the acetylated form remaining constant throughout the cell cycle as it does for most H3/H4 lysine residues, acetylation of H3-Lys-56 occurs in S phase and disappears during G2/M phase of the cell cycle (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar, 14Zhou H. Madden B.J. Muddiman D.C. Zhang Z. Biochemistry. 2006; 45: 2852-2861Crossref PubMed Scopus (63) Google Scholar). However, it is not clear how H3-Lys-56 acetylation is restricted to S phase of the cell cycle. Two NAD-dependent histone deacetylases (HDACs), Hst3 and Hst4, have been found to deacetylate H3-Lys-56 (15Maas N.L. Miller K.M. Defazio L.G. Toczyski D.P. Mol. Cell. 2006; 23: 109-119Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 16Celic I. Masumoto H. Griffith W.P. Meluh P. Cotter R.J. Boeke J.D. Verreault A. Curr. Biol. 2006; 16: 1280-1289Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar). Moreover, the expression of these two enzymes peaks at G2/M phase of the cell cycle when the levels of acetylated H3-Lys-56 are lowest, suggesting that H3-Lys-56 acetylation is regulated, at least in part, by the protein levels of H3-Lys-56 HDACs. Whether H3-Lys-56 HDACs are the only factors that regulate H3-Lys-56 acetylation during the progression of the cell cycle, however, is unknown. Recently, we and others have discovered that in the yeast Saccharomyces cerevisiae, Rtt109 is a unique HAT, sharing no sequence homology to any known HATs discovered so far, that acetylates H3-Lys-56 (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar, 18Driscoll R. Hudson A. Jackson S.P. Science. 2007; 315: 649-652Crossref PubMed Scopus (345) Google Scholar). In vitro, recombinant Rtt109 and Rtt109 complexes purified from yeast cells acetylate H3 but not H4 in H3/H4 tetramers, suggesting that Rtt109 specifically targets H3. Cells lacking Rtt109 lose H3-Lys-56 acetylation and are sensitive to DNA-damaging agents to a similar degree as cells expressing H3 mutants unable to be acetylated at lysine 56. In addition, RTT109 genetically interacts with several genes involved in DNA replication as well as with genes involved in double strand break repair (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar, 19Tong A.H. Lesage G. Bader G.D. Ding H. Xu H. Xin X. Young J. Berriz G.F. Brost R.L. Chang M. Chen Y. Cheng X. Chua G. Friesen H. Goldberg D.S. Haynes J. Humphries C. He G. Hussein S. Ke L. Krogan N. Li Z. Levinson J.N. Lu H. Menard P. Munyana C. Parsons A.B. Ryan O. Tonikian R. Roberts T. Sdicu A.M. Shapiro J. Sheikh B. Suter B. Wong S.L. Zhang L.V. Zhu H. Burd C.G. Munro S. Sander C. Rine J. Greenblatt J. Peter M. Bretscher A. Bell G. Roth F.P. Brown G.W. Andrews B. Bussey H. Boone C. Science. 2004; 303: 808-813Crossref PubMed Scopus (1650) Google Scholar, 20Suter B. Tong A. Chang M. Yu L. Brown G.W. Boone C. Rine J. Genetics. 2004; 167: 579-591Crossref PubMed Scopus (94) Google Scholar, 21Pan X. Ye P. Yuan D.S. Wang X. Bader J.S. Boeke J.D. Cell. 2006; 124: 1069-1081Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). These genetic interactions suggest that H3-Lys-56 acetylation mediated by Rtt109 is involved in DNA replication. However, it is not known whether Rtt109 acetylates H2A and H2B, or H3 when H3 is assembled into nucleosomes. Thus, here we report further biochemical characterization of this novel HAT. Rtt109 co-purifies with Vps75, a previously uncharacterized protein, from yeast cells (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar, 22Krogan N.J. Cagney G. Yu H. Zhong G. Guo X. Ignatchenko A. Li J. Pu S. Datta N. Tikuisis A.P. Punna T. Peregrin-Alvarez J.M. Shales M. Zhang X. Davey M. Robinson M.D. Paccanaro A. Bray J.E. Sheung A. Beattie B. Richards D.P. Canadien V. Lalev A. Mena F. Wong P. Starostine A. Canete M.M. Vlasblom J. Wu S. Orsi C. Collins S.R. Chandran S. Haw R. Rilstone J.J. Gandi K. Thompson N.J. Musso G. St Onge P. Ghanny S. Lam M.H. Butland G. Altaf-Ul A.M. Kanaya S. Shilatifard A. O'Shea E. Weissman J.S. Ingles C.J. Hughes T.R. Parkinson J. Gerstein M. Wodak S.J. Emili A. Greenblatt J.F. Nature. 2006; 440: 637-643Crossref PubMed Scopus (2338) Google Scholar). We have reconstituted recombinant Rtt109-Vps75 complexes, and these recombinant complexes display HAT activity toward H3. Moreover, both native Rtt109-Vps75 complexes purified from yeast cells and recombinant Rtt109-Vps75 complexes purified from bacteria acetylate only H3, but not other histones, and do so only when H3 is not assembled into nucleosomes. These results suggest that the reduction of H3-Lys-56 acetylation during G2/M phase of the cell cycle is mediated, at least in part, by the inability of Rtt109 to acetylate nucleosomal H3. Furthermore, the N-terminal tail domains of H3/H4 tetramers were found to be required for efficient binding of Rtt109 to histones and H3-Lys-56 acetylation by Rtt109-Vps75 complexes. Thus, these studies provide insights into the substrate requirements of Rtt109 as well as the cell cycle regulation of H3-Lys-56 acetylation. Generation of rtt109Δ and vps75Δ Strains—The rtt109Δ deletion strain was generated as described (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). Standard procedures were followed to delete the VPS75 gene through homologous recombination the was as described previously that specifically acetylated H3-Lys-56 H. Madden B.J. Muddiman D.C. Zhang Z. Biochemistry. 2006; 45: 2852-2861Crossref PubMed Scopus (63) Google Scholar). of Rtt109-Vps75 from were of yeast cells expressing Rtt109 or Vps75 at the with the tandem affinity and the were purified as described (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). of Histone H3/H4 H3/H4/H2A/H2B and H3/H4 tetramers were purified as described J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for the mutant H3/H4 tetramers were from H3 and the H4 B. Biochemistry. 2005; PubMed Scopus Google Scholar). H3 and H4 mutants were from the K. of and purified procedures similar to used to H3/H4 tetramers J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). H3/H4/H2A/H2B core histones were purified from cells procedures described by and Holde J. Holde K.E. Biochemistry. 25: PubMed Scopus Google Scholar). and of and were purified from of cells similar to for core histones J. Holde K.E. Biochemistry. 25: PubMed Scopus Google that the was not were from other nucleosome and or of and were Generation of Rtt109-Vps75 and of was and as described (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). VPS75 gene was DNA as for the VPS75 gene an the DNA sequence to the was for protein were used to Rtt109-Vps75 complexes. for Histone histone acetyltransferase of complexes were as described with (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). were at for in that and of of recombinant H3/H4 tetramers H3/H4/H2A/H2B core histones, H3/H4 tetramers or of and was as of was and were for with of and with of of was a protein was from were and were and to whether H3-Lys-56 was were with at for the and that H3 acetylated at lysine 56 was or bound to was with different of H3/H4 tetramers in a and at bound to or were and by with Coomassie Brilliant or H3. DNA were at in and to cells were and of the DNA-damaging or for cells were by a Vps75 a of the Rtt109 HAT a in S. to involved in acetylation of we recently the unique HAT Rtt109 (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). In addition, we an by others that Vps75, a previously uncharacterized protein, co-purifies with Rtt109 from yeast cells N.J. Cagney G. Yu H. Zhong G. Guo X. Ignatchenko A. Li J. Pu S. Datta N. Tikuisis A.P. Punna T. Peregrin-Alvarez J.M. Shales M. Zhang X. Davey M. Robinson M.D. Paccanaro A. Bray J.E. Sheung A. Beattie B. Richards D.P. Canadien V. Lalev A. Mena F. Wong P. Starostine A. Canete M.M. Vlasblom J. Wu S. Orsi C. Collins S.R. Chandran S. Haw R. Rilstone J.J. Gandi K. Thompson N.J. Musso G. St Onge P. Ghanny S. Lam M.H. Butland G. Altaf-Ul A.M. Kanaya S. Shilatifard A. O'Shea E. Weissman J.S. Ingles C.J. Hughes T.R. Parkinson J. Gerstein M. Wodak S.J. Emili A. Greenblatt J.F. Nature. 2006; 440: 637-643Crossref PubMed Scopus (2338) Google Scholar). this Rtt109-Vps75 complex HAT activity toward H3 and However, the vps75Δ mutant was not in as H3-Lys-56 acetylation (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google suggesting that Vps75 is not required for H3-Lys-56 acetylation in this we the VPS75 gene from yeast cells and H3-Lys-56 acetylation by shown in H3-Lys-56 acetylation was not to a degree in the vps75Δ mutant cells as with wild-type Furthermore, the vps75Δ mutant cells were not sensitive to DNA-damaging agents a displayed by cells with H3-Lys-56 acetylation (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar, J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). Thus, Vps75 is not required for H3-Lys-56 acetylation in yeast cells or for Rtt109 to acetylate H3-Lys-56 in (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar, 18Driscoll R. Hudson A. Jackson S.P. Science. 2007; 315: 649-652Crossref PubMed Scopus (345) Google Scholar). Vps75 is not required for H3-Lys-56 acetylation by Vps75 is a protein that co-purifies with Rtt109 and is not part of the Rtt109 HAT complex. whether Vps75 forms a complex with we to and a recombinant Rtt109-Vps75 complex. when Vps75 and Rtt109 were in a complex of Rtt109 and Vps75 was present throughout Moreover, these recombinant complexes displayed HAT activity toward H3 and Thus, these results that Vps75 is a of the Rtt109-Vps75 HAT with Rtt109 as the and Rtt109-Vps75 have shown that Rtt109-Vps75 complexes purified from yeast cells acetylate H3, but not when recombinant H3/H4 tetramers are used as (17Han J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar). Thus, we to the substrate requirements for Rtt109-Vps75 complexes both native complexes purified from yeast cells and recombinant complexes purified from E. we the of Rtt109-Vps75 complexes to acetylate H3/H4/H2A/H2B core histones purified from Rtt109-Vps75 complexes purified from yeast cells acetylated H3 present in core histone complexes, as both a binding and less efficiently than when H3 was present as a of recombinant H3/H4 tetramers. Moreover, the complex acetylated H3, but not H2B, or H4 and and suggesting that Rtt109-Vps75 complexes histone in In addition, the recombinant Rtt109-Vps75 complexes exhibited a similar degree of HAT activity as native complexes toward H3 when H3/H4 tetramers or H3/H4/H2A/H2B core histones were used as substrate and the acetylation of H3 by Rtt109-Vps75 complexes when H3 is present as a of core histones, we how Rtt109-Vps75 complexes acetylate acetylation of H3 by Rtt109-Vps75 complexes was more efficient when H3 was as H3/H4 tetramers, both recombinant and native complexes acetylated H3-Lys-56 to a similar degree of whether H3/H4 tetramers or H3/H4/H2A/H2B core histones were used as and in the of Rtt109-Vps75 complexes to acetylate H3 when present in H3/H4 tetramers H3/H4/H2A/H2B core histones does not to be to in the HAT activity of Rtt109-Vps75 complexes toward H3/H4 tetramers as with core histones is to acetylation of H3 lysine residues other than H3-Lys-56 that are for acetylation when as H3/H4 recombinant tetramers in but not when H3 is assembled with core histones. these H3 lysine residues acetylated by Rtt109-Vps75 complexes when H3 is a of H3/H4 tetramers be in H3/H4/H2A/H2B core histones by acetylation in cells, and as these lysine residues no be for acetylation by Rtt109-Vps75 complexes. Rtt109-Vps75 complexes exhibited reduced HAT activity toward core histones, of nucleosomes are we whether Rtt109-Vps75 complexes acetylate nucleosomal H3. this we purified as well as of and from cells and used these as for HAT native recombinant Rtt109-Vps75 complexes exhibited detectable HAT activity toward H3 present in or of and and and Rtt109-Vps75 complexes acetylate H3 when recombinant H3/H4 tetramers were with or of and the inability of Rtt109 to acetylate H3 when H3 is present as a of nucleosomes is not likely to with and Thus, these results that Rtt109-Vps75 complexes acetylate H3 only it is assembled into with that H3-Lys-56 acetylation is present on histones during S phase of the cell cycle (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar). N-terminal of H3 and H4 for Acetylation of H3-Lys-56 by in HAT exhibited by Rtt109-Vps75 complexes toward H3, on whether H3 was a of H3/H4 tetramers, core histones, or suggest that the in H3 is assembled is important for acetylation. Further, domains of H3 of the core domain acetylation of lysine 56. native Rtt109-Vps75 complexes not acetylate lysine 56 to a detectable degree when as an H3 comprising residues lysine 56 not We whether deletion of the N-terminal tail domains of both H3 and H4 the of native and recombinant Rtt109-Vps75 complexes to acetylate H3 as a of these H3/H4 tetramers. protein both native and recombinant Rtt109-Vps75 complexes acetylated H3/H4 tetramers more efficiently than H3/H4 tetramers, as by binding and and and acetylated H3-Lys-56 and of recombinant Rtt109-Vps75 complexes were however, H3-Lys-56 was acetylated in the of H3/H4 tetramers, but to a Thus, domains in to lysine 56 of H3, as the N-terminal tail domains of to be required for efficient acetylation of H3-Lys-56 by the Rtt109-Vps75 complex. N termini of H3 and H4 are from lysine 56 of H3. However, it is that acetylation of lysine residues at the N of H3 or H4 is required for H3-Lys-56 acetylation. Thus, we whether of lysine residues at the N of H3 and or lysine residues at the N of H4 and to H3-Lys-56 acetylation. with wild-type cells, H3-Lys-56 acetylation was not to a detectable degree in the H3 or the H4 N-terminal mutant cells suggesting that acetylation of these lysine residues is not a for H3-Lys-56 acetylation. we whether the N-terminal tail domains of H3/H4 tetramers be required for the binding of Rtt109 with histones a shown in bound to H3/H4 tetramers, the a S used as a Z. A. C. M. S. A. PubMed Scopus Google this we whether deletion of the N-terminal tail domains of H3/H4 the of with H3. shown in more H3 than H3. Thus, these results with that the N-terminal tail domains of H3/H4 tetramers to the of Rtt109 with histones, and the efficient acetylation of H3 by Rtt109-Vps75 complexes. In the present we have reconstituted Rtt109-Vps75 complexes recombinant and that Vps75 is an of the novel Rtt109-Vps75 HAT complex. both recombinant and native Rtt109-Vps75 complexes, we have shown that these HAT complexes acetylate H3 present in H3/H4/H2A/H2B core histones but not H3 present in nucleosomes. These results suggest that regulation of H3-Lys-56 acetylation during the cell cycle is mediated, in part, by the inability of Rtt109-Vps75 complexes to acetylate nucleosomal H3. Furthermore, we have shown that the N-terminal tail domains of H3/H4 tetramers to the binding of Rtt109 to histones and the efficient acetylation of H3-Lys-56 by Rtt109-Vps75 complexes in these results insights into the substrate requirements for this novel HAT complex. Rtt109 acetylate H3-Lys-56 in and in yeast cells in the of Thus, Vps75 is a of Rtt109-Vps75 complexes, it is not required for acetylation of Vps75 is homologous to the histone nucleosome assembly protein and the a of the inhibitor of acetyltransferases complex not We at least two to the function of Vps75 as a of the Rtt109 HAT complex. Vps75 function similar to by with histones, the binding affinity of Rtt109 for H3 and Rtt109-Vps75 complexes to acetylate H3 more Vps75 function the HAT activity of several HATs by binding to histones and a HAT from histone P. S. A. D. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, it is that Vps75 to lysine residues of H3 and Rtt109 from acetylating these lysine residues, the of Rtt109 toward lysine 56. studies these two Acetylation of H3-Lys-56 occurs during S phase of the cell cycle and disappears at G2/M phase (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar, 14Zhou H. Madden B.J. Muddiman D.C. Zhang Z. Biochemistry. 2006; 45: 2852-2861Crossref PubMed Scopus (63) Google Scholar). However, how this acetylation is regulated during the progression of the cell cycle is not studies here on the Rtt109-Vps75 complex with two recent studies on the H3-Lys-56 HDACs Hst3 and (15Maas N.L. Miller K.M. Defazio L.G. Toczyski D.P. Mol. Cell. 2006; 23: 109-119Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 16Celic I. Masumoto H. Griffith W.P. Meluh P. Cotter R.J. Boeke J.D. Verreault A. Curr. Biol. 2006; 16: 1280-1289Abstract Full Text Full Text PDF PubMed Scopus (249) Google suggest that are at least two to regulate H3-Lys-56 acetylation during progression of the cell cycle. when H3 is assembled into acetylation of H3-Lys-56 by Rtt109-Vps75 complexes is 56 of H3 is in the core domain of H3 at the of an and is in to DNA when H3 is assembled into nucleosomes K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Nature. 1997; 389: 251-260Crossref PubMed Scopus (6926) Google Scholar). Thus, it is that when H3 is assembled into lysine 56 of H3 is to Rtt109-Vps75 complexes. domains of H3/H4 in to in to as their N-terminal tail be in nucleosomes that the of Rtt109-Vps75 complexes to and the of Rtt109 to acetylate is studies as Rtt109-Vps75 complexes not acetylate nucleosomal H3, the of H3 as a of distinct complexes a for regulating H3-Lys-56 acetylation during the cell cycle. it has been that H3-Lys-56 acetylation is regulated by the protein levels of two H3-Lys-56 Hst3 and Hst4, these two HDACs are during G2/M phase of the cell cycle. Thus, the inability of Rtt109-Vps75 complexes to acetylate nucleosomal H3 with the expression levels of Hst3 and during G2/M phase of the cell cycle provide a means for regulating H3-Lys-56 acetylation during the cell cycle. Recently, J. P. S.R. Shilatifard A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google that Rtt109 is required for H3-Lys-56 acetylation and that this modification be involved in In addition, others have that H3-Lys-56 acetylation is at genes F. Zhang K. Grunstein M. Cell. 2005; 121: 375-385Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). However, acetylation of H3-Lys-56 occurs on histones (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google and several studies have that the primary function of Rtt109 and H3-Lys-56 acetylation is likely involved in DNA replication the DNA (10Masumoto H. Hawke D. Kobayashi R. Verreault A. Nature. 2005; 436: 294-298Crossref PubMed Scopus (490) Google Scholar, J. Zhou H. Horazdovsky B. Zhang K. Xu R.M. Zhang Z. Science. 2007; 315: 653-655Crossref PubMed Scopus (333) Google Scholar, 18Driscoll R. Hudson A. Jackson S.P. Science. 2007; 315: 649-652Crossref PubMed Scopus (345) Google Scholar, 21Pan X. Ye P. Yuan D.S. Wang X. Bader J.S. Boeke J.D. Cell. 2006; 124: 1069-1081Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). this we have shown that Rtt109-Vps75 HAT complexes no detectable activity toward H3 when H3 is assembled into nucleosomes. these results suggest that the of H3-Lys-56 acetylation at genes the S phase of this form of H3 this modification be involved in by histones with H3 acetylated at lysine 56. studies are to the distinct of H3-Lys-56 acetylation mediated by Rtt109 in DNA replication and We M. Thompson for of the for with for the expression of mutant H3/H4 and and for with

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