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Carcinogenesis induced by biological stresses

Research Project

Project/Area Number 20K21410
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

MASAI Hisao  公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 所長 (40229349)

Project Period (FY) 2020-07-30 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords熱ショック / 酸化ストレス / 浸透圧ストレス / 栄養ストレス / Claspin / Chk1 / DNA複製チェックポイント / 統合的ストレス応答 / NA複製チェックポイント / 複製障害 / 複製チェックポイント / ゲノム不安定性 / 生体ストレス
Outline of Research at the Start

発がんの過程は複雑であるが、がんの原因となるゲノム変動の大部分は、細胞周期進行において最も時間のかかるDNA複製 (6-8時間)の過程の不全により、直接・間接に引き起こされる。
我々は、種々の細胞に、種々の細胞ストレス(高温、酸化、浸透圧、低酸素、LPS等)を与えることにより(3時間)、Claspinに依存してChk1の活性化が起こることを発見した。この事実は、複製とは一見関連していない細胞ストレスを短時間与えることにより、複製障害が誘起され、複製ストレス応答経路が活性化される可能性を示唆する。
本申請では、種々の細胞ストレスにより、誘導される複製障害のメカニズムとそれによるがん化の可能性を検証する。

Outline of Final Research Achievements

Various biological stresses activate replication checkpoint. Some (high temperature, oxidative stress and arsenate) inhibit DNA replication, while others activate Chk1 without affecting replication. They activate Chk1 both in G1 and S phases in Claspin-independent and -dependent manners, respectively. Furthermore, GCN2, HRI kinases involved in Integrated stress response pathway are required for stress-induced Chk1 activation. These results suggest cross talks between replication checkpoint and stress-induced responses, pointing to a potential mechanism whereby biological stresses may induce genomic instability.

Academic Significance and Societal Importance of the Research Achievements

ストレスは、身体の機能に大きな影響を与える。一方、複製ストレスは、ゲノム不安定性の誘導を介して発がんの究極的な原因となる。細胞は、それを取りまく環境の変化(温度変化、酸素レベルの変動、細菌感染、酸化ストレスなど)に応答して、種々のシグナル経路を発動し、適応を図る。本研究成果では、環境ストレスと複製ストレスのcross talkの存在を証明し、生体ストレスの蓄積が、発がんなどの疾患に至る分子経路を明らかにした。これらの発見は、人の発がんの予防のための新たな方策を示唆する。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (30 results)

All 2023 2022 2021 2020 Other

All Journal Article (19 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 19 results,  Open Access: 19 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 8 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Histone Modification Analysis of Low-Mappability Regions2023

    • Author(s)
      Naoko Yoshizawa-Sugata , Hisao Masai
    • Journal Title

      Methods Mol Biol

      Volume: 2519 Pages: 163-185

    • DOI

      10.1007/978-1-0716-2433-3_18

    • ISBN
      9781071624326, 9781071624333
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Claspin is Required for Growth Recovery from Serum Starvation through Regulating the PI3K-PDK1-mTOR Pathway in Mammalian Cells2023

    • Author(s)
      Yang Chi-Chun、Masai Hisao
    • Journal Title

      Molecular and Cellular Biology

      Volume: 43 Issue: 1 Pages: 1-21

    • DOI

      10.1080/10985549.2022.2160598

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aberrant association of chromatin with nuclear periphery induced by Rif1 leads to mitotic defect2023

    • Author(s)
      Kanoh Yutaka、Ueno Masaru、Hayano Motoshi、Kudo Satomi、Masai Hisao
    • Journal Title

      Life Science Alliance

      Volume: 6 Issue: 4 Pages: e202201603-e202201603

    • DOI

      10.26508/lsa.202201603

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Claspin-Dependent and -Independent Chk1 Activation by a Panel of Biological Stresses2023

    • Author(s)
      Hsiao Hao-Wen、Yang Chi-Chun、Masai Hisao
    • Journal Title

      Biomolecules

      Volume: 13 Issue: 1 Pages: 125-125

    • DOI

      10.3390/biom13010125

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-inducible factor-1α and poly [ADP ribose] polymerase 1 cooperatively regulate Notch3 expression under hypoxia via a noncanonical mechanism2022

    • Author(s)
      Nakamura Hideaki、Sekine Hiroki、Kato Hiroyuki、Masai Hisao、Gradin Katarina、Poellinger Lorenz
    • Journal Title

      Journal of Biological Chemistry

      Volume: 298 Issue: 7 Pages: 102137-102137

    • DOI

      10.1016/j.jbc.2022.102137

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TT-pocket/HIRAN: binding to 3′-terminus of DNA for recognition and processing of stalled replication forks2022

    • Author(s)
      Masai Hisao
    • Journal Title

      The Journal of Biochemistry

      Volume: 172 Issue: 2 Pages: 57-60

    • DOI

      10.1093/jb/mvac042

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Replicon hypothesis revisited2022

    • Author(s)
      Masai Hisao
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 633 Pages: 77-80

    • DOI

      10.1016/j.bbrc.2022.09.060

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of full-length DNA replication regulator Rif1 in two-cell embryos is associated with zygotic transcriptional activation2021

    • Author(s)
      Yoshizawa-Sugata Naoko、Yamazaki Satoshi、Mita-Yoshida Kaoru、Ono Tomio、Nishito Yasumasa、Masai Hisao
    • Journal Title

      Journal of Biological Chemistry

      Volume: 297 Issue: 6 Pages: 101367-101367

    • DOI

      10.1016/j.jbc.2021.101367

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of Claspin in regulation of DNA replication, replication stress responses and oncogenesis in human cells2021

    • Author(s)
      Hsiao Hao-Wen、Yang Chi-Chun、Masai Hisao
    • Journal Title

      Genome Instability & Disease

      Volume: 2 Issue: 5 Pages: 263-280

    • DOI

      10.1007/s42764-021-00049-8

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of HP1 protein by phosphorylation during transcriptional repression and cell cycle2021

    • Author(s)
      Oki Masaya、Masai Hisao
    • Journal Title

      The Journal of Biochemistry

      Volume: - Issue: 6 Pages: 629-632

    • DOI

      10.1093/jb/mvab040

    • NAID

      40022686976

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers2021

    • Author(s)
      Irie Takayuki、Asami Tokiko、Sawa Ayako、Uno Yuko、Taniyama Chika、Funakoshi Yoko、Masai Hisao、Sawa Masaaki
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 64 Issue: 19 Pages: 14153-14164

    • DOI

      10.1021/acs.jmedchem.1c01319

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular DJ-1 induces sterile inflammation in the ischemic brain.2021

    • Author(s)
      Nakamura K, Sakai S, Tsuyama J, Nakamura A, Otani K, Kurabayashi K, Yogiashi Y, Masai H, Shichita T
    • Journal Title

      PLOS Biol

      Volume: 19 Issue: 5 Pages: e3000939-e3000939

    • DOI

      10.1371/journal.pbio.3000939

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition2021

    • Author(s)
      Kitajima Shojiro、Sun Wendi、Lee Kian Leong、Ho Jolene Caifeng、Oyadomari Seiichi、Okamoto Takashi、Masai Hisao、Poellinger Lorenz、Kato Hiroyuki
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 4538-4538

    • DOI

      10.1038/s41598-021-83857-y

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization.2020

    • Author(s)
      Kato H, Asamitsu K, Sun W, Kitajima S, Yoshizawa-Sugata N, Okamoto T, Masai H, Poellinger L
    • Journal Title

      Oncogene.

      Volume: 39 Issue: 16 Pages: 3322-3335

    • DOI

      10.1038/s41388-020-1218-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Detection of cellular G-quadruplex by using a loop structure as a structural determinant2020

    • Author(s)
      Masai Hisao、Kanoh Yutaka、Kakusho Naoko、Fukatsu Rino
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Issue: 1 Pages: 75-83

    • DOI

      10.1016/j.bbrc.2020.05.191

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] LDL-mimetic lipid nanoparticles prepared by surface KAT ligation for in vivo MRI of atherosclerosis2020

    • Author(s)
      Fracassi A, Cao J, Yoshizawa-Sugata N, Toth E, Archer C, Groninger O, Ricciotti E, S-Y Tang, Handschin S, Bourgeois J-P, Ray A, Liosi K, Oriana S, Stark W, Masai H, Zhou R, Yamakoshi Y
    • Journal Title

      Chem Sci

      Volume: -

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] G-quadruplexes: tools, roles, and goals2020

    • Author(s)
      Masai Hisao、Tan Zheng
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Issue: 1 Pages: 1-2

    • DOI

      10.1016/j.bbrc.2020.05.092

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] G-quadruplex DNA and RNA: Their roles in regulation of DNA replication and other biological functions2020

    • Author(s)
      Masai Hisao、Tanaka Taku
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Issue: 1 Pages: 25-38

    • DOI

      10.1016/j.bbrc.2020.05.132

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] G-quadruplex binding protein Rif1, a key regulator of replication timing2020

    • Author(s)
      Alavi Sana、Ghadiri Hamed、Dabirmanesh Bahareh、Moriyama Kenji、Khajeh Khosro、Masai Hisao
    • Journal Title

      The Journal of Biochemistry

      Volume: 169 Issue: 1 Pages: 1-14

    • DOI

      10.1093/jb/mvaa128

    • NAID

      40022490610

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Roles of G4 binding and multimization of Rif1 in S phase regulation in fission yeast cells.2021

    • Author(s)
      Hisao Masai, Yutaka Kanoh, Kaho Takasawa, Daisuke Koida, Seiji Matsumoto
    • Organizer
      Cold Spring Harbor Asia Conference YEAST AND LIFE SCIENCES
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Claspin is required for growth recovery from serum starvation through regulating the PI3K-PDK1-mTOR pathway.2021

    • Author(s)
      Chi-Chun Yang, Hisao Masai
    • Organizer
      Cold Spring Harbor Asia Conference, DNA METABOLISM, GENOMIC STABILITY & HUMAN DISEASE
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Mechanisms of membrane association of Rif1 and its role in replication timing regulation2021

    • Author(s)
      Tomohiro Iguchi, Sayuri Ito, Naoko Kokusho, Yutaka Kanoh, Kaho, Takasawa, Kenji Moriyama, Hiroyuki Sasanuma, Hisao Masai.
    • Organizer
      Cold Spring Harbor Laboratory Meeting EUKARYOTIC DNA REPLICATION & GENOME MAINTENANCE
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Chromatin regulation that involves assembly of protein, lipid and DNA with a special higher-order structure2021

    • Author(s)
      正井久雄
    • Organizer
      シンポジウム「染色体の多様な機能を支えるタンパク質高次複合体」第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Association of Rif1 with nuclear membrane is essential for genome-wide replication timing regulation2021

    • Author(s)
      Tomohiro Iguchi, Sayuri Ito, Naoko Kakusho, Satoshi Yamazaki, Asami Oji, Rino Fukatsu, Ichiro Hiratani, Hiroyuki Sasanuma, Hisao Masai
    • Organizer
      第44回日本分子生物学会年会 シンポジウム 「DNA構造ダイナミクスを基盤とするゲノム複製と維持の生物種を超えた共通原理」
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Genetic interaction network of BRCA2 tumor suppressor gene2021

    • Author(s)
      Hiroyuki Sasanuma, Kousei Yamada, Ngo Trinh, Hisao Masai, Kosuke Yusa
    • Organizer
      第44回日本分子生物学会年会 ワークショップ「ゲノム安定性:その破綻を誘導する分子機構と破綻によりおこるゲノム異常」
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Claspin, a key regulator of replication checkpoint, is differentially regulated in cancer and non-cancer cells.2020

    • Author(s)
      Yang Chi-Chun and Masai Hisao
    • Organizer
      11th international symposium on DNA Damage Response & Human Disease (isDDRHD-2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] グアニン4重鎖/RNA-DNAハイブリッド構造によるDNA複製の制御機構2020

    • Author(s)
      正井久雄
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] G4/RNA-DNAハイブリッドに依存する環状染色体DNAの複製機構2020

    • Author(s)
      正井 久雄 、 田中 卓 、鷺 朋子 、深津 理乃 、関 由美香
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] ゲノムに潜む未解明のシグナル、グアニン4重鎖(実験医学増刊号「セントラルドグマの新常識」)2022

    • Author(s)
      正井 久雄
    • Total Pages
      11
    • Publisher
      羊土社
    • ISBN
      9784758104043
    • Related Report
      2022 Annual Research Report
  • [Remarks] ゲノム動態プロジェクト

    • URL

      https://www.igakuken.or.jp/genome/

    • Related Report
      2022 Annual Research Report 2021 Research-status Report 2020 Research-status Report

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Published: 2020-08-03   Modified: 2024-01-30  

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