Updated on 2024/10/30

写真a

 
FUJITA MASATOSHI
 
Organization
Faculty of Pharmaceutical Sciences Department of Pharmaceutical Health Care and Sciences Professor
School of Pharmaceutical Sciences Department of Clinical Pharmacy(Concurrent)
Graduate School of Pharmaceutical Sciences Department of Clinical Pharmacy(Concurrent)
Graduate School of Pharmaceutical Sciences Department of Medicinal Sciences(Concurrent)
Title
Professor
Contact information
メールアドレス
Tel
0926426635
Profile
Chromosomal DNA Replication and Cancer Research In human cells, genomic DNA, which carries genetic information, has to be replicated faithfully, completely, and only once during a single cell cycle to maintain integrity. If some errors occur during copying DNA (DNA replication), then it would sometimes lead to bad consequences. “Cancer” is one and serious example resulting from such replication errors (mutations). Molecular mechanisms for cell cycle regulation of DNA replication initiation Several molecular mechanisms contribute to the maintenance of genomic integrity. Replicative DNA polymerases synthesize new daughter strand using complementary parental strand. However, DNA polymerases very rarely incorporate incorrect nucleotides. The mismatch repair pathway that removes inappropriate nucleotides is a fail-safe mechanism for such errors and the disturbance is well known to cause genomic instability and eventual cancer. Chromosomal DNAs are often damaged, for example by ultraviolet, which should also be repaired. Disruption of such repair mechanism also leads to cancer. We have been interested in elucidating molecular mechanisms for cell cycle regulation of DNA replication initiation, another crucial aspect of replication controls. In human cells, genomic DNA is fragmented into multiple chromosomes, which may allow genome size to expand during the evolution. As a result, DNA replication initiates from multiple replication origins. However, effective operation of the “multiple replication origin” system gives rise to an important problem: i.e. multiple replication origins should each be activated precisely only once during each S phase. Recent research progress by us and other groups has uncovered the mechanisms. It is now clear that the “once and only once replication per single cell cycle” is achieved by the periodic assembly and disassembly of pre-replication complexes (pre-RCs) at replication origins. The pre-RC assembly reaction, known as “licensing”, involves the loading of a presumptive replicative helicase, the MCM2-7 complex, onto chromatin by the origin recognition complex (ORC), CDC6 and Cdt1. Two critical inhibitory factors for the pre-RC assembly are cyclin/Cdks (Cdk1 and Cdk2) and geminin. During late mitosis through the G1 phase, a cell cycle regulatory E3 ubiquitin ligase APC/C restrains cyclins and geminin by targeting them for proteolysis through polyubiquitination. Thus, pre-RC assembly only occurs during this period. Following APC/C inactivation at the onset of S phase, Cdks are activated, stimulating DNA unwinding by MCM. Then, DNA polymerases synthesize new DNA. To prevent re-replication, the re-establishment of pre-RC, in other words re-binding of MCM, needs to be suppressed during the S, G2 and M phases of the cell cycle. Cdks play a central role also in this context by preventing re-establishment of pre-RC through multiple mechanisms. One is by phosphorylation of CDC6, leading to CDC6 nuclear export. ORC1 is degraded after S phase, presumably depending on phosphorylation by cyclin A/Cdks and binding to SCFSkp2 ubiquitin ligase. Cdt1, a central factor for the cell cycle regulation of replication initiation: Elucidating the strict regulations by three ubiquitin ligases It was originally suggested that inhibition of Cdt1 function after S phase is due to geminin binding. However, we have recently demonstrated that three ubiquitin ligases strictly control Cdt1 proteolysis, showing that Cdt1 is a central player in the cell cycle regulation of replication initiation. During S and G2 phases, Cdt1 is brought to proteolysis by Cdk phosphorylation-dependent SCFSkp2-mediated ubiquitination. Interestingly, Cdt1 is also regulated by replication-coupled, Cullin4-DDB1Cdt2 ubiquitin ligase-mediated ubiquitination, which is dependent on Cdt1 binding to PCNA, an eukaryotic sliding clamp stimulating DNA polymerases. In addition, when cells enter quiescence, Cdt1 is rapidly cleared by APC/CCdh1-mediated proteolysis. Cdt1 deregulation induces chromosomal instability, a mechanism leading to cancer As expected from the strict regulation, deregulation of Cdt1 is a deleterious insult, leading to re-replication and/or chromosomal damage. The induced chromosomal instability may eventually lead to carcinogenesis and Cdt1 overexpression is in fact often observed in human cancers. By other groups, it has been suggested that Cdt1 overexpression could endow cells with the transforming ability. Cdt1-geminin system could be a novel molecular target for anti-cancer chemotherapeutic agents We also think that tumor cells could be selectively eliminated by modulating the Cdt1-geminin interactions and have been seeking small molecule compounds that affect the interaction.
External link

Degree

  • MD, PhD

Research History

  • 愛知県がんセンター、国立がんセンター

Research Interests・Research Keywords

  • Research theme:Molecular mechanisms for cellular responses to chromosomal stress through ATM-Chk2 and ATR-Chk1 pathways and involvement of the replication initiation proteins in such process

    Keyword:replication stress、ATM、ATR、DNA replication initiation factors

    Research period: 2009.3

  • Research theme:Involvement of the replication initiation proteins in telomere homeostasis

    Keyword:DNA replication initiation factors, telomere

    Research period: 2006.3

  • Research theme:Search for Cdt1-geminin binding inhibitors that could selectively damage cancer cells by inducing re-replication

    Keyword:Cdt1-geminin inhibitor、anti-neoplastic drug

    Research period: 2006.3

  • Research theme:Function and regulation of DNA replication initiation proteins, ORC, CDC6, Cdt1 and MCM during the cell cycle

    Keyword:DNA replication, cell cycle regulation, replication initiation, ORC, CDC6, Cdt1, MCM

    Research period: 1996.4

Awards

  • 2021年度JB論文賞

    2021.11   日本生化学会   GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity

  • 日本癌学会奨励賞受賞

    2001.9   日本癌学会   ヒト細胞におけるDNA複製開始タンパク質の機能と細胞周期調節機構の解析

Papers

  • TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress Invited Reviewed International journal

    Higa, Mitsunori; Matsuda, Yukihiro; Fujii, Jumpei; Sugimoto, Nozomi; Yoshida, Kazumasa; Fujita, Masatoshi

    NUCLEIC ACIDS RESEARCH   49 ( 21 )   12234 - 12251   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1093/nar/gkab1004

  • SLX4-XPF mediates DNA damage responses to replication stress induced by DNA-protein interactions Invited Reviewed International journal

    Ishimoto R, Tsuzuki Y, Matsumura T, Kurashige S, Enokitani K, Narimatsu K, Higa M, Sugimoto N, Yoshida K, Fujita M.

    JOURNAL OF CELL BIOLOGY   220 ( 1 )   2021.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1083/jcb.202003148

  • Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10 Reviewed

    Takuya Yokoyama, Masaki Yukuhiro, Yuka Iwasaki, Chika Tanaka, Kazunari Sankoda, Risa Fujiwara, Atsushi Shibuta, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Kazumasa Yoshida, Nozomi Sugimoto, Hiroyuki Morimoto, Hidetaka Kosako, Takashi Ohshima, Masatoshi Fujita

    Scientific reports   9 ( 1 )   2019.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41598-019-53259-2

  • GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity Reviewed International journal

    Hiroki Fujiyama, Takahiro Tsuji, Kensuke Hironaka, Kazumasa Yoshida, Nozomi Sugimoto, and Masatoshi Fujita

    Journal of Biochemistry   2019.9

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1093/jb/mvz075

  • Inhibiting the MCM8-9 complex selectively sensitizes cancer cells to cisplatin and olaparib Reviewed

    Issay Morii, Yukiko Iwabuchi, Sumiko Mori, Masaki Suekuni, Toyoaki Natsume, Kazumasa Yoshida, Nozomi Sugimoto, Masato T. Kanemaki, Masatoshi Fujita

    Cancer Science   110 ( 3 )   1044 - 1053   2019.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1111/cas.13941

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Books

Presentations

  • ヒト染色体上における内因性複製ストレス誘導モデルを用いた修復因子SLX4-XPF複合体の局在制御機構 Invited

    勝木 陽子、岡野 拓真、藤井 純平、松村 友輝、吉田 和真、藤田 雅俊

    第46回日本分子生物学会年会シンポジウム  2023.12 

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    Event date: 2023.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:神戸市 神戸ポートアイランド   Country:Japan  

  • 蛋白質核酸複合体障害物により誘導される複製ストレスに対するSLX4-XPF-ATRを介したDNAダメージ応答におけるRAD52の役割 Invited

    藤田 雅俊、勝木 陽子、吉田 和真

    第46回日本分子生物学会年会シンポジウム  2023.12 

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    Event date: 2023.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:神戸市 神戸ポートアイランド   Country:Japan  

  • ヒト染色体上における内因性複製ストレス誘導モデルを用いた修復因子SLX4-XPF複合体の局在制御の解明 Invited

    勝木 陽子、岡野 拓真、藤井 純平、松村 友輝、吉田 和真、藤田 雅俊

    第96回日本生化学会大会シンポジウム  2023.11 

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    Event date: 2023.11

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

  • Molecular mechanism of the DDK-dependent MCM2-7 activation Invited International coauthorship

    Yasunori Noguchi, Almutasem Saleh, Sarah Schneider, Masatoshi Fujita and Christian Speck

    第96回日本生化学会大会シンポジウム  2023.11 

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    Event date: 2023.11

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

  • ポリメラーゼとヘリカーゼの解離を伴わない複製ストレスに対するDNAダメージ応答 Invited

    藤田 雅俊, 杉本 のぞみ, 吉田 和真

    第44回日本分子生物学会年会ワークショップ  2021.12 

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    Event date: 2022.12

    Language:Japanese  

    Venue:横浜市 パシフィコ横浜   Country:Japan  

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MISC

  • DNA damage response that enhance resilience to replication stress. Reviewed

    Yoshida, K. and Fujita, M.

    Cell. Mol. Life Sci.   2021.11

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: 10.1007/s00018-021-03926-3

  • GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins Reviewed

    Takuya Takafuji, Kota Kayama, Nozomi Sugimoto, Masatoshi Fujita

    Cell Cycle   2017.8

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: 10.1080/15384101.2017.1338987

  • DNA Replication Origins and Fork Progression at Mammalian Telomeres

    Mitsunori Higa, Masatoshi Fujita, Kazumasa Yoshida

    Genes (Basel). 2017 Mar 28;8(4). pii: E112. doi: 10.3390/genes8040112.   2017.3

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • 染色体動態制御と疾患の研究における新展開

    藤田雅俊

    蛋白質核酸酵素増刊「染色体サイクル」 54:552-555, 2009   1900

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

  • DNA Replication Initiation.

    Fujita M.

    Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine (edited by Ganten, D. and Ruckpaul, K.). Springer, Berlin Heidelberg & New York, pp446-449, 2006   1900

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

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Industrial property rights

Patent   Number of applications: 3   Number of registrations: 0
Utility model   Number of applications: 0   Number of registrations: 0
Design   Number of applications: 0   Number of registrations: 0
Trademark   Number of applications: 0   Number of registrations: 0

Professional Memberships

  • The Molecular Biology Society of Japan

  • Japanese Cancer Association

  • The Japanese Society of Internal Medicine

  • The Pharmaceutical Society of Japan

Committee Memberships

  • 日本薬学会   九州支部幹事   Domestic

    2014.4 - 2016.3   

  • Councilor   Domestic

    2008.1 - 2010.12   

Academic Activities

  • アドバイザー

    第22回 次世代を担う若手のためのファーマ・バイオフォーラム 2023  ( 福岡市 九州大学 ) 2023.9

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    Type:Competition, symposium, etc. 

  • Screening of academic papers

    Role(s): Peer review

    2023

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:3

  • Screening of academic papers

    Role(s): Peer review

    2023

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:6

  • Screening of academic papers

    Role(s): Peer review

    2022

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:4

  • オーガナイザー・座長

    第44回日本分子生物学会年会 ワークショップ  ( 横浜市 パシフィコ横浜 ) 2021.12

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    Type:Competition, symposium, etc. 

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Research Projects

  • 遺伝性骨髄不全症の登録システムの構築と診断基準・重症度分類・診断ガイドラインの確立に関する研究

    2023 - 2024

    科学研究費助成事業  厚生労働科学研究費補助金 (厚生労働省)

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    Authorship:Coinvestigator(s)  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • がん細胞選択的抗がん剤あるいはプラチナ製剤/PARP 阻害剤増感剤としてのMCM8-9 阻害性人工核酸アンチセンスオリゴDNAの開発

    2023

    令和5年度 橋渡し研究プログラム シーズ A (九州大学公募)

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    Authorship:Principal investigator  Grant type:On-campus funds, funds, etc.

  • 複製フォークとDNA-蛋白質複合体衝突により惹起される複製ストレス応答機構の解明

    Grant number:22H02603  2022 - 2025

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • MCM8-9を標的とした人工核酸アンチセンスオリゴDNAによるがん細胞選択的プラチナ製剤/PARP阻害剤増感療法の開発

    2022 - 2023

    安田記念医学財団 令和4年度癌研究助成金

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    Authorship:Principal investigator  Grant type:Contract research

  • 人工核酸アプタマーを利用したDNA損傷修復ヘリカーゼMCM8-9阻害剤探索によるがん選択的プラチナ製剤/PARP阻害剤増感療法開発

    2019

    西暦2019年度福岡県新製品・新技術創出研究開発支援事業に係る 可能性試験事業

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    Authorship:Principal investigator  Grant type:Contract research

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Class subject

  • 分子腫瘍学B

    2024.12 - 2025.2   Winter quarter

  • 分子腫瘍学A

    2024.10 - 2024.12   Fall quarter

  • 分子生物学

    2024.4 - 2024.9   First semester

  • 生命薬学ⅡA

    2024.4 - 2024.6   Spring quarter

  • 染色体生物学とそのがん研究への応用

    2024.4 - 2024.6   Spring quarter

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FD Participation

  • 2023.11   Role:Participation   Title:第2回部局FD講演会「機関間連携」

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2023.8   Role:Participation   Title:令和5年度4部局合同男女共同参画FD

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2022.11   Role:Participation   Title:第4回創薬産学官連携セミナー(アカデミア創薬)

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2022.11   Role:Participation   Title:第4回創薬産学官連携セミナー(アカデミア創薬)

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2022.4   Role:Participation   Title:学生の多様性に対応した教育とは:障害学生への合理的配慮を中心に

    Organizer:[Undergraduate school/graduate school/graduate faculty]

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Visiting, concurrent, or part-time lecturers at other universities, institutions, etc.

  • 2024  長崎大学・医学部  Classification:Part-time lecturer  Domestic/International Classification:Japan 

  • 2023  長崎大学・医学部  Classification:Part-time lecturer  Domestic/International Classification:Japan 

  • 2022  長崎大学・医学部  Classification:Part-time lecturer  Domestic/International Classification:Japan 

  • 2021  長崎大学・医学部  Classification:Part-time lecturer  Domestic/International Classification:Japan 

  • 2020  長崎大学・医学部  Classification:Part-time lecturer  Domestic/International Classification:Japan 

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Other educational activity and Special note

  • 2020  Class Teacher 

  • 2019  Class Teacher 

  • 2018  Class Teacher 

  • 2015  Special Affairs 

  • 2014  Class Teacher 

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Social Activities

  • 都民講座/ゲノム研究から明らかになった発がんの仕組みと、それを利用した新しいがん治療法の開発

    東京都医学総合研究所  2021.4

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 出前講座/生命の本質である遺伝情報を正確に受け渡すための仕組み—分子生物学的研究と抗がん剤開発への応用—

    福岡県立 明善高校  福岡県立 明善高校  2020.11

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 出前講座/生命の本質である遺伝情報を正確に受け渡すための仕組み—分子生物学的研究と抗がん剤開発への応用—

    福岡県立 明善高校  福岡県立 明善高校  2016.7

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 遺伝情報を過不足なく受け継ぐためのしくみー分子生物学的解明と抗がん剤開発への応用ー

    平成26年度福岡県理科・化学教育懇談会総会  福岡教育大学  2015.1

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 出前講座/ヒトの進化!がん細胞の進化? —分子生物学的研究から見えてくるもの—

    福岡県立 春日高校  福岡県立 春日高校  2010.10

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

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Media Coverage

  • 「未来に夢ある」がん医療 Newspaper, magazine

    世界日報  2021.5

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    「未来に夢ある」がん医療

Activities contributing to policy formation, academic promotion, etc.

  • 2023.12 - 2024.1   University of Toronto

    教授人事審査に関わる外部評価委員

  • 2023.10 - 2023.12   Science Foundation Ireland

    大型プロジェクト研究の審査(Frontiers for the Future Programme)

  • 2023.3   Dutch Research Council

    大型プロジェクト研究の審査(NWO Talent Programme – Veni scheme)

  • 2023.2   The Israel Science Foundation

    大型プロジェクト研究の審査(the Personal Research Grants)

  • 2022.6   山田科学振興財団

    研究助成金選考の外部査読

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Acceptance of Foreign Researchers, etc.

  • チュラロンコン大学

    Acceptance period: 2023.3 - 2023.6  

    Nationality:Thailand

  • Chulalongkorn University

    Acceptance period: 2019.5 - 2019.6  

    Nationality:Thailand

  • ナレスアン大学

    Acceptance period: 2018.6 - 2018.8  

    Nationality:Thailand

  • コンケン大学

    Acceptance period: 2017.6 - 2017.8  

    Nationality:Thailand

  • ナレスアン大学

    Acceptance period: 2016.6 - 2016.8  

    Nationality:Thailand

Travel Abroad

  • 2015.9

    Staying countory name 1:United States   Staying institution name 1:Cold Spring Harbor Laboratory Meeting on Eukaryotic DNA Replication & Genome Maintenance

  • 2013.9

    Staying countory name 1:United States   Staying institution name 1:Cold Spring Harbor Laboratory Meeting on Eukaryotic DNA Replication & Genome Maintenance

  • 2011.9

    Staying countory name 1:United States   Staying institution name 1:Cold Spring Harbor Laboratory Meeting on Eukaryotic DNA Replication & Genome Maintenance

  • 2009.10

    Staying countory name 1:Australia   Staying institution name 1:Keystone Symposia “ Telomere Biology and DNA Repair”

  • 2008.7

    Staying countory name 1:United States   Staying institution name 1:The Meeting on DNA Replication and Genome Integrity at Salk Institute

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