Homeodomain interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ

• Material Type: 博士論文
• Title: Homeodomain interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ
• Author/Editor: Akaike, Yoko; Kuwano, Yuki; Nishida, Kensei; Kurokawa, Ken; Kajita, Keisuke; Kano, Shizuka; Masuda, Kiyoshi; Rokutan, Kazuhito
• Author Heading: Akaike, Yoko; Kuwano, Yuki; Nishida, Kensei; Kurokawa, Ken; Kajita, Keisuke; Kano, Shizuka; Masuda, Kiyoshi; Rokutan, Kazuhito
• Publication, Distribution, etc.: Springer Nature
• Publication Date: 2014-08-25
• Publication Date (W3CDTF): 2014-08-25
• Alternative Title: Homeodomain interacting protein kinase 2はheterochromatin protein 1γとの相互作用を介してDNA損傷応答を制御する; HP1γ as a novel target for HIPK2
• Periodical title: Oncogene
• No. or year of volume/issue: 34 26
• Volume: 34
• Issue: 26
• Pages: 3463-3473
• ISSN (Periodical Title): ISSN : 1476-5594; ISSN : 0950-9232
• Degree grantor/type: 徳島大学
• Date Granted: 2014-03-24
• Dissertation Number: 甲第2672号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: DNA damage response; HIPK2; HP1γ; chromatin remodeling; DNA damage repair
• Target Audience: 一般
• Note (General): Homeodomain-interacting protein kinase 2 (HIPK2) is a potential tumor suppressor that plays a crucial role in the DNA damage response (DDR) by regulating cell cycle checkpoint activation and apoptosis. However, it is unclear whether HIPK2 exerts distinct roles in DNA damage repair. The aim of this study was to identify novel target molecule(s) of HIPK2, which mediates HIPK2-dependent DNA damage repair. HIPK2-knockdown human colon cancer cells (HCT116) or hipk1/hipk2 double-deficient mouse embryonic fibroblasts could not remove histone H2A.X phosphorylated at Ser139 (γH2A.X) after irradiation with a sublethal dose (10 J/m2) of ultraviolet (UV)-C, resulting in apoptosis. Knockdown of HIPK2 in p53-null HCT116 cells similarly promoted the UV-C-induced γH2A.X accumulation and apoptosis. Proteomic analysis of HIPK2-associated proteins using liquid chromatography-tandem mass spectrometry identified heterochromatin protein 1γ (HP1γ) as a novel target for HIPK2. Immunoprecipitation experiments with HCT116 cells expressing FLAG-tagged HIPK2 and one of the HA-tagged HP1 family members demonstrated that HIPK2 specifically associated with HP1γ, but not with HP1α or HP1β, through its chromo-shadow domain. Mutation of the HP1box motif (883-PTVSV-887) within HIPK2 abolished the association. HP1γ knockdown also enhanced accumulation of γH2A.X and apoptosis after sublethal UV-C irradiation. In vitro kinase assay demonstrated an HP1γ-phosphorylating activity of HIPK2. Sublethal UV-C irradiation phosphorylated HP1γ. This phosphorylation was absent in endogenous HIPK2-silenced cells with HIPK2 3’UTR siRNA. Overexpression of FLAG-HIPK2, but not the HP1box-mutated or kinase-dead HIPK2 mutant, in the HIPK2-silenced cells increased HP1γ binding to trimethylated (Lys9) histone H3 (H3K9me3), rescued the UV-C-induced phosphorylation of HP1γ, triggered release of HP1γ from histone H3K9me3, and suppressed γH2A.X accumulation. Our results suggest that HIPK2-dependent phosphorylation of HP1γ may participate in the regulation of dynamic interaction between HP1γ and histone H3K9me3 to promote DNA damage repair. This HIPK2/HP1γ pathway may uncover a new functional aspect of HIPK2 as a tumor suppressor.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1038/onc.2014.278
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/10/106072/20170929145331378525/LID201404221016.pdf fulltext

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