title: Identification of small molecules that inhibit the histone chaperone Asf1 and its chromatin function.
abstract: The eukaryotic genome is packed into chromatin, which is important for the genomic integrity and gene regulation. Chromatin structures are maintained through assembly and disassembly of nucleosomes catalyzed by histone chaperones. Asf1 (anti-silencing function 1) is a highly conserved histone chaperone that mediates histone transfer on/off DNA and promotes histone H3 lysine 56 acetylation at globular core domain of histone H3. To elucidate the role of Asf1 in the modulation of chromatin structure, we screened and identified small molecules that inhibit Asf1 and H3K56 acetylation without affecting other histone modification. These pyrimidine-2,4,6-trione derivative molecules inhibited the nucleosome assembly mediated by Asf1 in vitro, and reduced the H3K56 acetylation in HeLa cells. Furthermore, production of HSV viral particles was reduced by these compounds. As Asf1 is implicated in genome integrity, cell proliferation, and cancer, current Asf1 inhibitor molecules may offer an opportunity for the therapeutic development for treatment of diseases.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Ja-Hwan
authors.initials: JH
authors.lastname: Seol
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Tae-Yang
authors.initials: TY
authors.lastname: Song
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Oh
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Chanhee
authors.initials: C
authors.lastname: Jo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Ahreum
authors.initials: A
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Byungho
authors.initials: B
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Suji
authors.initials: S
authors.lastname: Hong
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Ilrang
authors.initials: I
authors.lastname: Song
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Kwan Young
authors.initials: KY
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: C491641:ASF1A protein, human; C491640:ASF1B protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D018832:Molecular Chaperones; D009707:Nucleosomes; D054852:Small Molecule Libraries