title: UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation.
abstract: Histone acetyltransferase binding to ORC-1 (HBO1) is a critically important histone acetyltransferase for forming the prereplicative complex (pre-RC) at the replication origin. Pre-RC formation is completed by loading of the MCM2-7 heterohexameric complex, which functions as a helicase in DNA replication. HBO1 recruited to the replication origin by CDT1 acetylates histone H4 to relax the chromatin conformation and facilitates loading of the MCM complex onto replication origins. However, the acetylation status and mechanism of regulation of histone H3 at replication origins remain elusive. HBO1 positively regulates cell proliferation under normal cell growth conditions. Whether HBO1 regulates proliferation in response to DNA damage is poorly understood. In this study, we demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were phosphorylated in an ATM/ATR DNA damage sensor-dependent manner after UV treatment. ATM/ATR-dependently phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4(DDB2). Replacement of endogenous HBO1 in Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV irradiation. Our findings demonstrate that HBO1 is one of the targets in the DNA damage checkpoint. These results show that ubiquitin-dependent control of the HBO1 protein contributes to cell survival during UV irradiation.
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Matsunuma
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan niidah@hama-med.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Niida
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ohhata
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan Research Equipment Center, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchida
authors.affiliation: Department of Cellular and Molecular Biology, Hiroshima University, Hiroshima, Japan.
authors.forename: Bunsyo
authors.initials: B
authors.lastname: Shiotani
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ogura
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Shiiya
authors.affiliation: Department of Molecular Biology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects*; D004249:DNA Damage / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects*; D017354:Point Mutation; D060066:Protein Interaction Maps; D055550:Protein Stability / Q000528:radiation effects; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000528:radiation effects; D014466:Ultraviolet Rays; D053722:Receptors, Interleukin-17
chemical_list: D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C117669:DDB2 protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C496553:KAT7 protein, human