Mechanisms of transcriptional repression in response to genome stress-role of histone H3 phosphorylation at T11-

• Project/Area Number: 20390083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagoya City University
• Principal Investigator: NAKANISHI Makoto Nagoya City University, 大学院・医学研究科, 教授 (40217774)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 遺伝子 / 核酸 / 癌 / 発現制御

Research Abstract

In this study, we found that dephosphorylation of histone H3-pT11 (H3-pT11) plays an essential role in DNA damage-induced transcriptional repression of various E2F-targeting genes. In the absence of DNA damage, Chk1/GCN5 complexes bound to E2Fs and cooperatively catalyzed T11 phosphorylation and K9 acetylation on E2F promoters, thereby activating their transcription. In the presence of DNA damage, Chk1/GCN5 complexes released from E2Fs and in place, Rb-PP1 gamma-HDAC3 complexes bound to E2Fs, leading to dephosphorylation of T11 and deacetylation of K9, which resulted in the transcriptional repression of E2F-targeting genes.

Research Products

• [Journal Article] PP1g is a phosphatase responsible for dephosphorylation of histone H3 at threonine 11 after DNA damage. (2010)
  • Author(s): Shimada, M., Haruta, M., Niida, H., Sawamoto, K., Nakanishi, M.
  • Journal Title: EMBO rep 11 Pages: 883-889
  • Peer Reviewed
• [Journal Article] Mechanisms of dNTP supply that play an essential role in maintaining genome integrity in eukaryotic cells. (2010)
  • Author(s): Niida, H., Shimada, M., Murakami, H., Nakanishi, M.
  • Journal Title: Cancer Sci 101 Pages: 2505-2509
  • NAID: 10027834110
  • Peer Reviewed
• [Journal Article] Cooperative functions of Chk1 and Chk2 reduce tumor susceptibility in vivo. (2010)
  • Author(s): Niida, H., Murata, K., Shimada, M., Ogawa, K., Ohta, K., Suzuki, K., Fujigaki, H., Khaw, A.K., Banerjee, B., Hande, P.M., Miyamoto, T., Miyoshi, I., Shirai, T., Motoyama, N., Delhase, M., Appella, E., Nakanishi, M.
  • Journal Title: EMBO J. 29 Pages: 3558-3570
  • Peer Reviewed
• [Journal Article] Regulation of yeast forkhead transcription factors and FoxM1 by cyclin-dependent and polo-like kinases. (2010)
  • Author(s): Murakami, H., Aiba, H., Nakanishi, M., Murakami-Tonami, Y.
  • Journal Title: Cell Cycle 9 Pages: 3233-3242
  • Peer Reviewed
• [Journal Article] Dual mode of regulation of cell division cycle 25A protein by TRB3. (2010)
  • Author(s): Sakai, S., Ohoka, N., Onozaki, K., Kitagawa, M., Nakanishi, M., Hayashi, H.
  • Journal Title: Biol Pharm Bull 33 Pages: 1112-1116
  • Peer Reviewed
• [Journal Article] Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. (2010)
  • Author(s): Niida, H., Katsuno, Y., Sengoku, M., Shimada, M., Yukawa, M., Ikura, M., Ikura, T., Kohno, K., Shima, H., Suzuki, H., Tashiro, S., Nakanishi, M.
  • Journal Title: Genes and Dev 24 Pages: 333-338
  • NAID: 130007000033
  • Peer Reviewed
• [Journal Article] Anaphase promoting complex/cyclosome-cdh1 mediates the ubiquitination and degradation of TRB3. (2010)
  • Author(s): Ohoka, N., Sakai, S., Onozaki, K., Nakanishi, M., Hayashi, H.
  • Journal Title: Biochem. Biophys. Res. Commun 392 Pages: 289-294
  • Peer Reviewed
• [Journal Article] Chk1-cycline A/Cdk1 axis regulates origin firing programs in mammals. (2010)
  • Author(s): Nakanishi, M., Katsuno, Y., Niida, H., Murakami, H., Shimada, M.
  • Journal Title: Chromosomal Res 18 Pages: 103-113
  • Peer Reviewed
• [Journal Article] PP1g is a phosphatase responsible for dephosphorylation of histone H3 at threonine 11 after DNA damage. (2010)
  • Author(s): Shimada, M., Haruta, M., Niida, H., Sawamoto, K., Nakanishi, M.
  • Journal Title: EMBO rep. Volume: 11 Pages: 883-889
  • Peer Reviewed
• [Journal Article] Mechanisms of dNTP supply that play an essential role in maintaining genome integrity in eukaryotic cells. (2010)
  • Author(s): Niida, H., Shimada, M., Murakami, H., Nakanishi, M.
  • Journal Title: Cancer Sci. Volume: 101 Pages: 2505-2509
  • NAID: 10027834110
  • Peer Reviewed
• [Journal Article] Cooperative functions of Chk1 and Chk2 reduce tumor susceptibility in vivo. (2010)
  • Author(s): Niida, H., Murata, K., Shimada, M., Ogawa, K., Ohta, K., Suzuki, K., Fujigaki, H., Khaw, A.K., Banerjee, B., Hande, P.M., Miyamoto, T., Miyoshi, I., Shirai, T., Motoyama, N., Delhase, M., Appella, E., Nakanishi, M.
  • Journal Title: EMBO J. Volume: 29 Pages: 3558-3570
  • Peer Reviewed
• [Journal Article] Regulation of yeast forkhead transcription factors and FoxM1 by cyclin-dependent and polo-like kinases. (2010)
  • Author(s): Murakami, H., Aiba, H., Nakanishi, M., Murakami-Tonami, Y.
  • Journal Title: Cell Cycle Volume: 9 Pages: 3233-3242
  • Peer Reviewed
• [Journal Article] Dual mode of regulation of cell division cycle 25A protein by TRB3. (2010)
  • Author(s): Sakai, S., Ohoka, N., Onozaki, K., Kitagawa, M., Nakanishi, M., Hayashi, H.
  • Journal Title: Biol Pharm Bull. Volume: 33 Pages: 1112-1116
  • Peer Reviewed
• [Journal Article] Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. (2010)
  • Author(s): Niida, H., Katsuno, Y., Sengoku, M., Shimada, M., Yukawa, M., Ikura, M., Ikura, T., Kohno, K., Shima, H., Suzuki, H., Tashiro, S., Nakanishi, M.
  • Journal Title: Genes and Dev. Volume: 24 Pages: 333-338
  • NAID: 130007000033
  • Peer Reviewed
• [Journal Article] Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase (2010)
  • Author(s): Niida, H.
  • Journal Title: Genes and Dev. 24 Pages: 333-338
  • Peer Reviewed
• [Journal Article] Anaphase promoting complex/cyclosome-cdh1 mediates the ubiquitination and degradation of TRB3 (2010)
  • Author(s): Ohoka, N.
  • Journal Title: Biochem.Biophys.Res.Commun. 18 Pages: 103-113
  • Peer Reviewed
• [Journal Article] Regulation of origin firing program in mammals through Chk1-cyclin A/Cdk1 axis (2010)
  • Author(s): Nakanishi, M.
  • Journal Title: Chromosomal Res. 18 Pages: 103-113
  • Peer Reviewed
• [Journal Article] DNA damage responses in skin biology-Implications in tumor prevention and aging acceleration. (2009)
  • Author(s): Nakanishi, M., Niida, H., Murakami, H., Shimada, M.
  • Journal Title: J Dermatol Sci 56 Pages: 76-81
  • NAID: 10025560903
  • Peer Reviewed
• [Journal Article] Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast. (2009)
  • Author(s): Shimada,M.,Yamamoto,A., Murakami-Tonami, Y., Nakanishi, M., Yoshida, T., Aiba, H., Murakami, H.
  • Journal Title: Biochem. Biophys. Res. Commun 388 Pages: 529-532
  • Peer Reviewed
• [Journal Article] Ptpcd-1 is a novel cell cycle related phosphatase that regulates centriole duplication and cytokinesis. (2009)
  • Author(s): Zineldeen, D.H., Shimada, M., Niida, H., Katsuno, Y., Nakanishi, M.
  • Journal Title: Biochem. Biophys. Res. Commun 380 Pages: 460-466
  • Peer Reviewed
• [Journal Article] Disruption of the novel gene fad14 causes rapid postnatal death and attenuation of cell proliferation, adhesion, spreading and migration. (2009)
  • Author(s): Nishizuka, M., Kishimoto, K., Kato, A., Ikawa, M., Okabe, M., Sato, R., Niida, H., Nakanishi, M., Osada, S., Imagawa, M.
  • Journal Title: Exp. Cell Res 315 Pages: 809-819
  • Peer Reviewed
• [Journal Article] Cyclin A-Cdk1 regulates the origin firing program in mammalian cells. (2009)
  • Author(s): Katsuno, Y., Suzuki, A., Sugimura, K., Okumura, K., Zineldeen, D.H., Shimada, M., Niida, H., Mizuno, T., Hanaoka, F., Nakanishi, M.
  • Journal Title: Proc. Natl. Acad. Sci 106 Pages: 3184-3189
  • Peer Reviewed
• [Journal Article] DNA damage responses in skin biology-lmplications in tumor prevention and aging acceleration (2009)
  • Author(s): Nakanishi, M.
  • Journal Title: J Dermatol Sci. 56 Pages: 333-338
  • Peer Reviewed
• [Journal Article] Casein kinase II is required for the spindle assembly check point by regulating Mad2p in fission yeast (2009)
  • Author(s): Shimada, M.
  • Journal Title: Biochem.Biophys.Res.Commun. 388 Pages: 529-532
  • Peer Reviewed
• [Journal Article] Ptpcd-1 is a novel cell cycle related phosphatase that regulates centriole duplication and cytokinesis (2009)
  • Author(s): Zineldeen, D.H.
  • Journal Title: Biochem.Biophys.Res.Commun. 380 Pages: 460-466
  • Peer Reviewed
• [Journal Article] Ptpcd-1 is a novel cell cycle related phosphatase that regulates centriole duplication and cytokinesis. (2009)
  • Author(s): Zineldeen, D. H.
  • Journal Title: Biochem. Biophys. Res. Commun. 380 Pages: 460-466
  • Peer Reviewed
• [Journal Article] Disruption of the novel gene fad14 causes rapid postnatal death and attenuation of cell proliferation, adhesion, spreading and migration. (2009)
  • Author(s): Nishizuka, M.
  • Journal Title: Exp. Cell Res. 315 Pages: 809-819
  • Peer Reviewed
• [Journal Article] Cyclin A-Cdk1 regulates the origin firing program in mammalian cells. (2009)
  • Author(s): Katsuno, Y.
  • Journal Title: Proc. Natl. Acad. Sci. 106 Pages: 3184-3189
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer. (2008)
  • Author(s): Nagata, D., Hashimoto, Y., Nakanishi, M., Naruyama, H., Okada, S., Ando, R., Tozawa, K., Kohri, K.
  • Journal Title: Cancer Detect Prev 32 Pages: 259-266
  • Peer Reviewed
• [Journal Article] Essential role of Chk1 in S phase progression through regulation of RNR2 expression. (2008)
  • Author(s): Naruyama, H., Shimada, M., Niida, H., Zineldeen, D.H., Hashimoto, Y., Kohri, K., Nakanishi, M.
  • Journal Title: Biochem. Biophys. Res. Commun 374 Pages: 79-83
  • Peer Reviewed
• [Journal Article] Checkpoints meet transcription at a novel histone milestone (H3-T11). (2008)
  • Author(s): Shimada, M., Nakanishi, M.
  • Journal Title: Cell Cycle 7 Pages: 1555-1559
  • Peer Reviewed
• [Journal Article] Susceptibility of p27 kip1 knockout mice to urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosami ne may not simply be due to enhanced proliferation. (2008)
  • Author(s): Hikosaka, A., Ogawa, K., Sugiura, S., Asamoto, M., Takeshita, F., Sato, S.Y., Nakanishi, M., Kohri, K., Shirai, T.
  • Journal Title: Int. J. Cancer 122 Pages: 1222-1228
  • Peer Reviewed
• [Journal Article] Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. (2008)
  • Author(s): Shimada, M., Niida, H., Zineldeen, D.H., Tagami, H., Tanaka, M., Saito, H., Nakanishi, M.
  • Journal Title: Cell 132 Pages: 221-232
  • Peer Reviewed
• [Journal Article] Cdc2p controls the forkhead transcription factor Fkh2 by phosphorylation during sexual differentiation in fission yeast. (2008)
  • Author(s): Shimada, M., Yamada-Namikawa, C., Murakami-Tonami, Y., Yoshida, T., Nakanishi, M., Urano, T., Murakami, H.
  • Journal Title: EMBO J. 27 Pages: 132-142
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer. (2008)
  • Author(s): Nagata, D.
  • Journal Title: Cancer Detect Prev. 32 Pages: 259-266
  • Peer Reviewed
• [Journal Article] Essential role of Chk1 in S phase progression through regulation of RNR2 expression. (2008)
  • Author(s): Naruyama, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 374 Pages: 79-83
  • Peer Reviewed
• [Journal Article] Checkpoints meet transcription at a novel histone milestone (H3-T11). (2008)
  • Author(s): Shimada, M.
  • Journal Title: Cell Cycle 7 Pages: 1555-1559
  • Peer Reviewed
• [Journal Article] Susceptibility of p27 kip1 knockout mice to urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine may not simply be due to enhanced proliferatio. (2008)
  • Author(s): Hikosaka, A.
  • Journal Title: Int. J. Cancer 122 Pages: 1222-1228
  • Peer Reviewed
• [Journal Article] Chkl is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. (2008)
  • Author(s): Shimada, M.
  • Journal Title: Cell 132 Pages: 221-232
  • Peer Reviewed
• [Journal Article] Cdc2p controls the forkhead transcription factor Fkh2 by phosphorylation during sexual differentiation in fission ye ast. (2008)
  • Author(s): Shimada, M.
  • Journal Title: EMBOJ. 27 Pages: 132-142
  • Peer Reviewed
• [Journal Article]
  • Author(s): Mizutani, E., Suzumori, N., Ozaki, Y., Oseto, K., Yamada-Namikawa, C., Nakanishi, M., Sugiura-Ogasawara, M.
  • Journal Title: Hum Reprod In press
  • Peer Reviewed
• [Journal Article] Novel Findings for the Development of Drug Therapy for Various Liver Diseases : Genetic Variation in IL-28B Is Associated With Response to the Therapy for Chronic Hepatitis C.
  • Author(s): Sugiyama, M., Tanaka, Y., Nakanishi, M., Mizokami, M.
  • Journal Title: J Pharmacol Sci in press
  • NAID: 10029892326
  • Peer Reviewed
• [Journal Article]
  • Author(s): Mizutani, E., Suzumori, N., Ozaki, Y., Oseto, K., Yamada-Namikawa, C., Nakanishi, M., Sugiura-Ogasawara, M.
  • Journal Title: Hum Reprod. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Novel Findings for the Development of Drug Therapy for Various Liver Diseases : Genetic Variation in IL-28B Is Associated With Response to the Therapy for Chronic Hepatitis C.
  • Author(s): Sugiyama, M., Tanaka, Y., Nakanishi, M., Mizokami, M.
  • Journal Title: J Pharmacol Sci. Volume: (In press)
  • NAID: 10029892326
  • Peer Reviewed
• [Presentation] Chk1-GCN5 とPP1g-HDAC3 複合体によるヒストンバイナリーコードの変換はDNA 損傷によるE2F 標的遺伝子の発現を抑制する (2010)
  • Author(s): 中西真、島田緑、春田真由美
  • Organizer: 2010日本分子生物、生化学会合同会議シンポジウム
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2010-12-10
• [Presentation] Chk1-GCN5とPP1g-HDAC3複合体によるヒストンバイナリーコードの変換はDNA損傷によるE2F標的遺伝子の発現を抑制する (2010)
  • Author(s): 中西真
  • Organizer: 2010日本分子生物、生化学会合同会議 シンポジウム
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2010-12-10
• [Presentation] 癌と細胞周期 (2010)
  • Author(s): 中西真
  • Organizer: 第69回日本癌学会総会ガン研究入門コース
  • Place of Presentation: 大阪国際会議場
• [Presentation] 癌と細胞周期 (2010)
  • Author(s): 中西真
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 大阪国際会議場
• [Presentation] DNA 損傷部位への適切なdNTP 供給機構 (2009)
  • Author(s): 中西真
  • Organizer: 第68回日本癌学会学術総会パシフィコ
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] DNA損傷部位への適切なdNTP供給機構 (2009)
  • Author(s): 中西真
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-10-02
• [Presentation] DNA損傷応答における新たなヒストン修飾H3-T11のリン酸化を介した転写制御 (2008)
  • Author(s): 中西 真
  • Organizer: 第31回分子生物学会年会、第81回日本生化学学会大会合同大会シンポジウム
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2008-12-09
• [Presentation] 細胞周期と発がん (2008)
  • Author(s): 中西 真
  • Organizer: 第67回日本癌学会学術総会シンポジウム
  • Place of Presentation: 名古屋市センチュリーホール
  • Year and Date: 2008-10-28
• [Presentation] 細胞周期と発がん (2008)
  • Author(s): 中西真
  • Organizer: 第67回日本癌学会学術総合シンポジウム
  • Place of Presentation: 名古屋白鳥センチュリーホール
• [Presentation] DNA 損傷応答における新たなヒストン修飾H3-T11 のリン酸化を介した転写制御 (2008)
  • Author(s): 中西真
  • Organizer: 第31回分子生物学会年会、第81回日本生化学学会大会合同大会シンポジウム
  • Place of Presentation: 神戸ポートアイランド
• [Book] Checkpoint Controls and Targets in Cancer Therapy(Chapter6) (2008)
  • Author(s): Nakanishi, M.
  • Publisher: Human Press.