title: Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B).
abstract: 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 (anti-silencing 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.
authors.affiliation: From the Department of Biochemistry & Biophysics, Abramson Family Cancer Research Institute, and.
authors.forename: Allison
authors.initials: A
authors.lastname: Haigney
authors.affiliation: From the Department of Biochemistry & Biophysics, Abramson Family Cancer Research Institute, and the Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Ricketts
authors.affiliation: From the Department of Biochemistry & Biophysics, Abramson Family Cancer Research Institute, and marmor@mail.med.upenn.edu.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation
chemical_list: C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; D006657:Histones; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D051548:Histone Acetyltransferases; C110880:histone acetyltransferase type B complex
keywords: acetyltransferase; gene regulation; histone acetylation; histone chaperone; protein complex