title: Ubinuclein-1 confers histone H3.3-specific-binding by the HIRA histone chaperone complex.
abstract: Histone chaperones bind specific histones to mediate their storage, eviction or deposition from/or into chromatin. The HIRA histone chaperone complex, composed of HIRA, ubinuclein-1 (UBN1) and CABIN1, cooperates with the histone chaperone ASF1a to mediate H3.3-specific binding and chromatin deposition. Here we demonstrate that the conserved UBN1 Hpc2-related domain (HRD) is a novel H3.3-specific-binding domain. Biochemical and biophysical studies show the UBN1-HRD preferentially binds H3.3/H4 over H3.1/H4. X-ray crystallographic and mutational studies reveal that conserved residues within the UBN1-HRD and H3.3 G90 as key determinants of UBN1-H3.3-binding specificity. Comparison of the structure with the unrelated H3.3-specific chaperone DAXX reveals nearly identical points of contact between the chaperone and histone in the proximity of H3.3 G90, although the mechanism for H3.3 G90 recognition appears to be distinct. This study points to UBN1 as the determinant of H3.3-specific binding and deposition by the HIRA complex.
authors.affiliation: 1] Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Ricketts
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Frederick
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Hoff
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.affiliation: 1] Institute of Cancer Sciences, CR-UK Beatson Labs, University of Glasgow, Glasgow G61 1BD, UK [2] Institute of Biomedical and Environmental Health Research, University of West of Scotland, Paisley PA1 2BE, UK.
authors.forename: Taranjit
authors.initials: T
authors.lastname: Singh Rai
authors.affiliation: Institute of Cancer Sciences, CR-UK Beatson Labs, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Vizioli
authors.affiliation: Institute of Cancer Sciences, CR-UK Beatson Labs, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: 1] Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin; D056970:Co-Repressor Proteins; D003460:Crystallization; D018360:Crystallography, X-Ray; D056488:Histone Chaperones / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins; D061987:Sf9 Cells; D018411:Spodoptera; D014157:Transcription Factors / Q000378:metabolism*; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C491641:ASF1A protein, human; D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C406814:UBN1 protein, human; D029867:Xenopus Proteins