Hif1 Is a Component of Yeast Histone Acetyltransferase B, a Complex Mainly Localized in the Nucleus

Poveda, Ana; Pamblanco, Mercè; Tafrov, Stefan T.; Tordera, Vicente; Sternglanz, Rolf; Sendra, Ramón

doi:10.1074/jbc.m314228200

Cited by 101 publications

(171 citation statements)

References 64 publications

(125 reference statements)

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“…The purified protein was crystallized in complex with AcCoA and histone H4 peptide (residues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. After an initial screen, we used the alkylated enzyme to improve crystal quality.…”

Section: Resultsmentioning

confidence: 99%

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Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1

Moshkina

Min

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4. Here we report a 1.9-Å resolution crystal structure of human histone acetyltransferase 1 in complex with acetyl coenzyme A and histone H4 peptide. The crystal structure reveals that the cofactor and the side chain of lysine 12 of histone H4 peptide are placed in the canyon between the central and C-terminal domains. Histone H4 peptide adopts a well-defined conformation and establishes an extensive set of interactions with the enzyme including invariant residues Glu64 and Trp199, which together govern substrate-binding specificity of histone acetyltransferase 1. Our structure-guided enzyme kinetic study further demonstrates a cumulative effect of the active-site residues Glu187, Glu276, and Asp277 on deprotonation of the ɛ-amino group of reactive Lys12 for direct attack of the acetyl group of the cofactor.

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Section: Resultsmentioning

confidence: 99%

“…Subsequent studies showed that HAT1 is predominantly localized in the nucleus (3)(4)(5)(6) where it forms a trimeric complex with HAT2 and the histone chaperone HIF1. HIF1 is detected exclusively in the nucleus and accompanies newly modified H3-H4 tetramers to facilitate their incorporation into nascent chromatin during DNA synthesis.…”

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confidence: 99%

Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1

Moshkina

Min

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…It is interesting to note that HAT1, which acetylates Lys-5 and Lys-12 on newly synthesized soluble histone H4, was originally termed the cytoplasmic HAT (31, 32), although it is now known to be mostly nuclear (33). However, it is still a matter of debate as to where the acetylation of soluble histones occurs, and there is evidence that H4 is acetylated in the cytoplasm (34).…”

Section: Asf1 Is Likely To Present the Newly Synthesized Freementioning

confidence: 99%

The Histone Chaperone Anti-silencing Function 1 Stimulates the Acetylation of Newly Synthesized Histone H3 in S-phase

Adkins

Carson

English

et al. 2007

Journal of Biological Chemistry

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Anti-silencing function 1 (Asf1) is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair. We have found that budding yeast lacking Asf1 has greatly reduced levels of histone H3 acetylated at lysine 9. Lysine 9 is acetylated on newly synthesized budding yeast histone H3 prior to its assembly onto newly replicated DNA. Accordingly, we found that the vast majority of H3 Lys-9 acetylation peaked in S-phase, and this S-phase peak of H3 lysine 9 acetylation was absent in yeast lacking Asf1. By contrast, deletion of ASF1 has no effect on the S-phase specific peak of H4 lysine 12 acetylation; another modification carried by newly synthesized histones prior to chromatin assembly. We show that Gcn5 is the histone acetyltransferase responsible for the S-phase-specific peak of H3 lysine 9 acetylation. Strikingly, overexpression of Asf1 leads to greatly increased levels of H3 on acetylation on lysine 56 and Gcn5-dependent acetylation on lysine 9. Analysis of a panel of Asf1 mutations that modulate the ability of Asf1 to bind to histones H3/H4 demonstrates that the histone binding activity of Asf1 is required for the acetylation of Lys-9 and Lys-56 on newly synthesized H3. These results demonstrate that Asf1 does not affect the stability of the newly synthesized histones per se, but instead histone binding by Asf1 promotes the efficient acetylation of specific residues of newly synthesized histone H3.The eukaryotic genome is packaged into a nucleoprotein structure known as chromatin. The basic repeating unit of chromatin, the nucleosome, is made up of 147 base pairs of DNA wrapped around a histone octamer (two molecules each of histone proteins H2A, H2B, H3, and H4) (1). Chromatin provides a formidable obstacle to the cellular machinery gaining access to the DNA. Indeed, it is becoming apparent that chromatin is a highly dynamic structure that tightly regulates all nuclear processes that use DNA as a substrate; including transcription, DNA replication, repair, and recombination (2-4). Thus, the mechanisms by which chromatin structures are made and modified are fundamental questions of broad interest.The entire eukaryotic genome is assembled into chromatin following DNA replication, and this occurs in a stepwise manner; a tetramer of histones H3/H4 is deposited first followed by two dimers of H2A/H2B on the outside of the tetramer. Histone-binding proteins, termed histone chaperones, mediate chromatin assembly. It is known that when this process is coupled to DNA replication in vitro, it is mediated by the histone H3/H4 chaperone chromatin assembly factor 1 (CAF-1) 2 (5) together with another H3/H4 chaperone termed anti-silencing function 1 (Asf1) (6). CAF-1 and Asf1 have also been shown to localize to the sites of DNA replication (7, 8), supporting a role in assembling chromatin following DNA replication in vivo. The fact that CAF-1 and Asf1 co-purify with the replicationspecific histone variant H3.1 from HeLa cells is further evidence that Asf1 ...

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“…The protein Hif1, similar to Hat2, is a histone H3-H4 specific chaperone and was initially identified as a component of the HAT-B complex where it has been hypothesized to be responsible for recruiting histones H3-H4 to HAT-B. Deletion experiments have shown that the loss of Hif1 in combination with K9R and K14R mutations in H3 is comparable to deletion of Hat1, which results in defects of telomeric silencing and DNA double-stranded break repair (19). The association of the histone chaperone Hif1 with HAT-B was the first direct evidence implicating a role for Hat1 in the chromatin assembly process (17).…”

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confidence: 99%

Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B)

Haigney

Ricketts

Marmorstein

2015

Journal of Biological Chemistry

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The HAT-B enzyme complex is responsible for acetylating newly synthesized histone H4 on lysines K5 and K12. HAT-B is a multisubunit complex composed of the histone acetyltransferase 1 (Hat1) catalytic subunit and the Hat2 (rbap46) histone chaperone. Hat1 is predominantly localized in the nucleus as a member of a trimeric NuB4 complex containing Hat1, Hat2, and a histone H3-H4 specific histone chaperone called Hif1 (NASP). In addition to Hif1 and Hat2, Hat1 interacts with Asf1 (antisilencing function 1), a histone chaperone that has been reported to be involved in both replication-dependent and -independent chromatin assembly. To elucidate the molecular roles of the Hif1 and Asf1 histone chaperones in HAT-B histone binding and acetyltransferase activity, we have characterized the stoichiometry and binding mode of Hif1 and Asf1 to HAT-B and the effect of this binding on the enzymatic activity of HAT-B. We find that Hif1 and Asf1 bind through different modes and independently to HAT-B, whereby Hif1 binds directly to Hat2, and Asf1 is only capable of interactions with HAT-B through contacts with histones H3-H4. We also demonstrate that HAT-B is significantly more active against an intact H3-H4 heterodimer over a histone H4 peptide, independent of either Hif1 or Asf1 binding. Mutational studies further demonstrate that HAT-B binding to the histone tail regions is not sufficient for this enhanced activity. Based on these data, we propose a model for HAT-B/histone chaperone assembly and acetylation of H3-H4 complexes.Histone acetylation has been linked to diverse functions including transcriptional activation, gene silencing, DNA repair, cell cycle progression, chromatin maturation and dynamics, and nucleosome assembly (1, 2). There are two main classes of enzymes responsible for acetylation of histones: type A and type B histone acetyltransferases. Type A histone acetyltransferases are nuclear enzymes that acetylate histones in the context of chromatin, whereas type B acetyltransferases are responsible for the acetylation of newly synthesized histones H3 and H4. Although histone H3 is only moderately acetylated upon its synthesis (ϳ30%) (3, 4), newly synthesized histone H4 is highly acetylated on lysine residues K5 (H4K5) and K12 (H4K12) (3, 5, 6). These modifications are transient, and once transported across the nucleus, the histones are deacetylated during the course of chromatin maturation (7). Although acetylation of H4K5/12 is highly conserved throughout evolution, it has been shown to be nonessential through mutagenic analysis, in which replacing these residues with arginine (mimicking the constitutively unacetylated state) has no effect on cell growth in yeast (8). Thus the evolutionarily conserved function of H4K5/ K12 acetylation remains unknown.The HAT-B 2 enzyme complex is responsible for acetylating newly synthesized histone H4 on lysines K5 and K12 (9 -13). HAT-B is a multisubunit complex composed of histone acetyltransferase 1 (Hat1), the catalytic subunit, and Hat2 (rbap46), a histone chaperone that in...

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Hif1 Is a Component of Yeast Histone Acetyltransferase B, a Complex Mainly Localized in the Nucleus

Cited by 101 publications

References 64 publications

Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1

Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1

The Histone Chaperone Anti-silencing Function 1 Stimulates the Acetylation of Newly Synthesized Histone H3 in S-phase

Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B)

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