The molecular mechanism of cellular genescence

2010 Fiscal Year Final Research Report

• Project/Area Number: 21689010
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Nagoya City University
• Principal Investigator: SHIMADA Midori Nagoya City University, 大学院・医学研究科, 講師 (60444981)
• Project Period (FY): 2009 – 2010
• Keywords: 細胞周期 / DNA損傷 / チェックポイント

Research Abstract

Transcriptional repression of E2F1 target genes is regulated by rapid reduction of histone H3-T11 phosphorylation, which is mediated at least in part by DNA damage induced Chk1 dissociation from chromatin. However, molecular mechanism(s) how this dephosphorylation triggers transcriptional repression remains elusive. Here, we identify an 'acetyl/phospho' cassette at H3-K9/T11 on E2F promoters, which is switched by replacement of Chk1-GCN5 complexes with protein phosphatase 1 (PP1)-HDACs complexes scaffolded on Rb-family pocket proteins. PP1 activity toward T11 dephosphorylation is regulated by Cdk1-dependent phosphorylation of PP1 at T311. Under unperturbed condition, Chk1/GCN5 complex existed on E2F1 promoters. After DNA damage, PP1/HADCs complex on pRb was recruited to E2F1. Our results thus suggest that T11 phosphorylation may function as a phospho-acceptor targeted by ATR-Chk1 axis and accelerate K9 acetylation, which is reversed by the activation of PP1 and recruitment of HDACs bound to Rb-related proteins by Chk1-dependent inhibition of Cdks after DNA damage.

Research Products

• [Journal Article] PP1γ 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] 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 AK, Banerjee B, Hande P, 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] 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
  • 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
  • Peer Reviewed
• [Journal Article] Regulation of origin firing program in mammals through Chk1-cyclin A/Cdk1 axis. (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] 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.2009 56 Pages: 76-81
  • 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] Cyclin A-Cdk1 regulates the origin firing program in mammalian cells. (2009)
  • Author(s): Katsuno Y, Suzuki A, Sugimura K, Okumura K, Zineldeen DH, Shimada M, Niida H, Mizuno T, Hanaoka F, Nakanishi M.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 106 Pages: 3184-3189
  • Peer Reviewed
• [Journal Article] Ptpcd-1 is a novel cell cycle related phosphatase that regulates centriole duplication and cytokinesis. (2009)
  • Author(s): Zineldeen DH, Shimada M, Niida H, Katsuno Y, Nakanishi M.
  • Journal Title: Biochem.Biophys.Res.Commun. 380 Pages: 460-466
  • Peer Reviewed
• [Presentation] Histone binary switch mediated by Chk1-HAT and PP1-HDAC regulates DNA damage induced transcriptional repression (2010)
  • Author(s): Shimada M
  • Organizer: The 20^<th> Hot Spring Harbor Symposium in Japan
  • Place of Presentation: Fukuoka
  • Year and Date: 2010-08-20
• [Book] 細胞老化とチェックポイント(細胞周期フロンティア) (2010)
  • Author(s): 島田緑、中西真
  • Total Pages: 114-118
  • Publisher: 共立出版
• [Remarks] ホームページ等
  • URL: http://www.med.nagoya-cu.ac.jp/w3med/research/reports/results/001.html