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Study of ATRX mediated telomere maintenance in neuroblastoma by using genome editing technology (CRISPR/Cas9)

Research Project

Project/Area Number 18K15256
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionResearch Institute for Clinical Oncology Saitama Cancer Center

Principal Investigator

AKTER JESMIN  地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 技師 (70795830)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords神経芽腫 / ATRX / TP53 / FANCD2 / Neuroblastoma / Replication stress / G-quadruplex / p53 / ALT / ATM/Chk2/p53 / Telomerase
Outline of Final Research Achievements

Genetic aberrations are frequently present in the ATRX gene in older high-risk neuroblastoma (NB) patients with very poor clinical outcomes. Its loss-of-function strongly linked to replication stress (RS) and DNA damage through G-quadruplex (G4) DNA secondary structures. However, limited information is available on ATRX alteration-related NB tumorigenesis. We herein knocked out ATRX in MYCN-amplified (NGP) and single copy (SK-N-AS) NB cells with wild-type (wt) and truncated TP53 at the C terminus, respectively, using CRISPR/Cas9 systems. We revealed that ATRX depletion in TP53 wt NB cells was associated with an increased frequency of DSBs and a subsequent RS-induced DNA damage response, which was impaired by the loss of p53 through the activation of G4 DNA helicases or the FA DNA repair pathway protein, FANCD2. Therefore, it indicates that p53 deficiency limits ATRX loss-induced RS/and genome instability in NB cells by regulating DNA repair mechanisms and replication fork stability.

Academic Significance and Societal Importance of the Research Achievements

ATRX変異は予後不良な神経芽腫(NB)でしばしば見られる。本研究から、ATRXがゲノムの完全性を維持していること、ATRX欠損神経芽腫細胞の複製ストレスによるDNA傷害が、TP53欠損によりDNA修復機構と複製フォークの安定化により緩和されること、その機構にFANCD2タンパク質が主要な役割を果たすことが示された。このことから、FANCD2がATRXが欠損した神経芽腫に対する治療標的となりうることが示唆された。このように本研究の成果から、神経芽腫の腫瘍発生におけるATRX遺伝子変異の意義についての理解が深まり、高リスク神経芽腫に対する個別化医療のための重要な知見が得られた。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2021 2020 2019 2018

All Journal Article (5 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma2021

    • Author(s)
      Akter Jesmin、Katai Yutaka、Sultana Parvin、Takenobu Hisanori、Haruta Masayuki、Sugino Ryuichi P.、Mukae Kyosuke、Satoh Shunpei、Wada Tomoko、Ohira Miki、Ando Kiyohiro、Kamijo Takehiko
    • Journal Title

      Oncogenesis

      Volume: 10 Issue: 11 Pages: 1256-1256

    • DOI

      10.1038/s41389-021-00363-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?2021

    • Author(s)
      Akter Jesmin、Kamijo Takehiko
    • Journal Title

      Biomolecules

      Volume: 11 Issue: 8 Pages: 1112-1112

    • DOI

      10.3390/biom11081112

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NLRR1 Is a Potential Therapeutic Target in Neuroblastoma and MYCN-Driven Malignant Cancers2021

    • Author(s)
      Takatori Atsushi、Hossain MD. Shamim、Ogura Atsushi、Akter Jesmin、Nakamura Yohko、Nakagawara Akira
    • Journal Title

      Frontiers in Oncology

      Volume: 11 Pages: 669667-669667

    • DOI

      10.3389/fonc.2021.669667

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Programmed expression of pro-apoptotic BMCC1 during apoptosis, triggered by DNA damage in neuroblastoma cells.2019

    • Author(s)
      Islam MS, Takano R, Yokochi T, Akter J, Nakamura Y, Nakagawara A, Tatsumi Y.
    • Journal Title

      BMC Cancer.

      Volume: 19 Issue: 1 Pages: 542-542

    • DOI

      10.1186/s12885-019-5772-4

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications2018

    • Author(s)
      Li Zhenghao、Takenobu Hisanori、Setyawati Amallia Nuggetsiana、Akita Nobuhiro、Haruta Masayuki、Satoh Shunpei、Shinno Yoshitaka、Chikaraishi Koji、Mukae Kyosuke、Akter Jesmin、Sugino Ryuichi P.、Nakazawa Atsuko、Nakagawara Akira、Aburatani Hiroyuki、Ohira Miki、Kamijo Takehiko
    • Journal Title

      Oncogene

      Volume: 37 Issue: 20 Pages: 2714-2727

    • DOI

      10.1038/s41388-018-0133-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] p53 deficiency limits ATRX loss induced replication stress and genome instability in neuroblastoma cells2020

    • Author(s)
      AKTER JESMIN
    • Organizer
      The 79th annual meeting of the Japanese Cancer Association
    • Related Report
      2020 Research-status Report
  • [Presentation] Genetic inactivation of ATRX can induces ATM dependent DNA damage response in neuroblastoma (NB) cells2018

    • Author(s)
      AKTER JESMIN
    • Organizer
      The 77th annual meeting of the Japanese Cancer Association
    • Related Report
      2018 Research-status Report
  • [Presentation] ATM/CHK2/P53 PATHWAY INACTIVATION IS REQUIRED FOR ATRX-MUTATION-RELATED TUMORIGENESIS2018

    • Author(s)
      AKTER JESMIN
    • Organizer
      50th Congress of the International society of Pediatric Oncology (SIOP)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] CRISPR-Cas9システムを用いた神経芽腫におけるATRX欠損の影響2018

    • Author(s)
      Yutaka Katai
    • Organizer
      The 41st Annual Meeting of the Molecular Biology Society of Japan
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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