Tumorigenesis by aberrant maintenance DNA methylation

• Project/Area Number: 26250027
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: The University of Tokyo (2016); Nagoya City University (2014-2015)
• Principal Investigator: Nakanishi Makoto 東京大学, 医科学研究所, 教授 (40217774)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥40,430,000 (Direct Cost: ¥31,100,000、Indirect Cost: ¥9,330,000); Fiscal Year 2016: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2015: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2014: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
• Keywords: DNAメチル化 / ゲノム不安定性 / DNA複製 / DNAM維持メチル化 / Dnmt1 / ユビキチン化 / ヒストンH3 / DNAメチル化異常 / 発がん / 癌 / 老化 / 分化

Outline of Final Research Achievements

Dnmt1 specifically binds to two mono ubiquitylated histone H3 such as H3K18Ub/K23/Ub, K14Ub/K18Ub, and K14Ub/K23Ub. The crystal structure of the replication foci targeting sequence (RFTS) of Dnmt1 in complex with H3-K18Ub/23Ub reveals striking differences to the previously identified ubiquitin-recognition structures.The binding of H3-K18Ub/23Ub results in spatial rearrangement of two lobes in the RFTS, suggesting the opening of its active site. Actually, incubation of Dnmt1 with H3-K18Ub/23Ub increases its catalytic activity in vitro. DNA hypomethylation by Dnmt1 knockdown results in an aberrant DNA replication program, leading to genomic instability.

Research Products

• [Int'l Joint Research] キュリー研究所(フランス)
• [Int'l Joint Research] キュリー研究所(フランス)
• [Journal Article] Usp7-dependent histone H3 deubiquitylation regulates maintenance of DNA methylation. (2017)
  • Author(s): Yamaguchi L, Nishiyama A, Misaki T, Johmura Y, Ueda J, Arita K, Nagao K, Obuse C, Nakanishi M
  • Journal Title: Scientific reports Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-017-00136-5
  • Peer Reviewed / Open Access
• [Journal Article] A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. (2017)
  • Author(s): Negishi Y, Miya F, Hattori A, Johmura Y, Nakagawa M, Ando N, Hori I, Togawa T, Aoyama K, Ohashi K, Fukumura S, Mizuno S, Umemura A, Kishimoto Y, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Nakanishi M, Saitoh S.
  • Journal Title: BMC Med Genet. Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12881-016-0363-6
  • Peer Reviewed / Open Access
• [Journal Article] HP1 regulates the localization of FANCJ at sites of DNA double-strand breaks. (2016)
  • Author(s): Wu W, Togashi Y, Johmura Y, Miyoshi Y, Nobuoka S, Nakanishi M, Ohta T.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 10 Pages: 1406-1415
  • DOI: 10.1111/cas.13008
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple facets of p53 in senescence induction and maintenance. (2016)
  • Author(s): Johmura Y, Nakanishi M.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 11 Pages: 1550-1555
  • DOI: 10.1111/cas.13060
  • Peer Reviewed / Open Access
• [Journal Article] Aurora B twists on histones for activation (2016)
  • Author(s): Shimada M and Nakanishi M
  • Journal Title: Cell Cycle Volume: 15 Issue: 24 Pages: 3321-3321
  • DOI: 10.1080/15384101.2016.1224758
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. (2016)
  • Author(s): Johmura Y, Yamashita E, Shimada M, Nakanishi K, Nakanishi M.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 31194-31194
  • DOI: 10.1038/srep31194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization. (2016)
  • Author(s): Kato K, Satouh Y, Nishimasu H, Kurabayashi A, Morita J, Fujihara Y, Oji A, Ishitani R, Ikawa M, Nureki O.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 12198-12198
  • DOI: 10.1038/ncomms12059
  • NAID: 120006957420
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Plasma membrane/cell wall perturbation activates a novel cell cycle checkpoint during G1 in S. cerevisiae. (2016)
  • Author(s): Kono K, Al-Zain A, Schroeder L, Nakanishi M, Ikui AE.
  • Journal Title: Proc. Natl. Acad, Sci. U. S. A. Volume: 113 Issue: 25 Pages: 6910-6915
  • DOI: 10.1073/pnas.1523824113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of Endogenous Retroviruses in Dnmt1-/- ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA. (2016)
  • Author(s): Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada M, Katsuyama K, Goyal P, Brind'Amour J, Sun MA, Sun Z, Ishikura T, Mizutani-Koseki Y, Ohara O, Shinkai Y, Nakanishi M, Xie H, Lorincz MC, Koseki H.
  • Journal Title: Cell Stem Cell Volume: Epub ahead of print Issue: 1 Pages: 999-999
  • DOI: 10.1016/j.stem.2016.03.013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. (2016)
  • Author(s): Johmura Y, Sun J, Kitagawa K, Nakanishi K, Kuno T, Naiki-Ito A, Sawada Y, Miyamoto T, Okabe A, Aburatani H, Li S-F, Miyoshi I, Takahashi S, Kitagawa M, Nakanishi M.
  • Journal Title: Nat. Commun. Volume: 7 Issue: 1 Pages: 10574-10574
  • DOI: 10.1038/ncomms10574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The replication foci targeting sequence (RFTS) of DNMT1 functions as a potent histone H3 binding domain regulated by autoinhibition. (2016)
  • Author(s): Misaki T, Yamaguchi L, Sun J, Orii M, Nishiyama A, Nakanishi M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 470 (3) Issue: 3 Pages: 741-747
  • DOI: 10.1016/j.bbrc.2016.01.029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PP1-Dependent Formin Bnr1 Dephosphorylation and Delocalization from a Cell Division Site (2016)
  • Author(s): Orii M, Kono K, Wen HI, Nakanishi M.
  • Journal Title: PLOS ONE Volume: 11 Issue: 1 Pages: e0146941-e0146941
  • DOI: 10.1371/journal.pone.0146941
  • Peer Reviewed / Open Access
• [Journal Article] Loss of maintenance DNA methylation results in abnormal DNA origin firing during DNA replication (2016)
  • Author(s): Haruta M, Shimada M, Nishiyama A, Johmura Y, Le Tallec B, Debatisse M, Nakanishi M
  • Journal Title: Biochem Biophys Res Commun Volume: 469 Issue: 4 Pages: 960-966
  • DOI: 10.1016/j.bbrc.2015.12.090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physical interaction between MPP8 and PRC1 complex and its implication for regulation of spermatogenesis (2015)
  • Author(s): Kazuhiro Murata, Shinya Sato, Myumi Haruta, Takahiro Goshima, Yoshie Chiba, Satoru Takahashi, Jafar Sharif, Haruhiko Koseki, Makoto Nakanishi, Midori Shimada
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 458 Issue: 3 Pages: 470-475
  • DOI: 10.1016/j.bbrc.2015.01.122
  • Peer Reviewed
• [Journal Article] Genotyping Analysis for the 46 C/T Polymorphism of Coagulation Factor XII and the Involvement of Factor XII Activity in Patients with Recurrent Pregnancy Loss. (2014)
  • Author(s): Asano E, Ebara T, Yamada-Namikawa C, Kitaori T, Suzumori N, Katano K, Ozaki Y, Nakanishi M, Sugiura-Ogasawara M.
  • Journal Title: PLoS One. Volume: 9 Issue: 12 Pages: e114452-e114452
  • DOI: 10.1371/journal.pone.0114452
  • Peer Reviewed / Open Access
• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction. (2014)
  • Author(s): Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S, Nakanishi M.
  • Journal Title: Mol.Cell Volume: 55 Issue: 1 Pages: 73-84
  • DOI: 10.1016/j.molcel.2014.05.003
  • Peer Reviewed
• [Journal Article] CBP-93872 inhibits NBS1-mediated ATR activation, abrogating maintenance of the DNA double-strand break-specific G2 checkpoint. (2014)
  • Author(s): Hirokawa T, Shiotani B, Shimada M, Murata K, Johmura Y, Haruta M, Tahara H, Takeyama H, Nakanishi M.
  • Journal Title: Cancer Res. Volume: 74 Issue: 14 Pages: 3880-9
  • DOI: 10.1158/0008-5472.can-13-3604
  • Peer Reviewed / Open Access
• [Journal Article] Mutational analysis of FOXL2 p.C134W and expression of bone morphogenetic protein 2 in Japanese patients with granulosa cell tumor of ovary. (2014)
  • Author(s): Oseto K, Suzumori N, Nishikawa R, Nishikawa H, Arakawa A, Ozaki Y, Asai H, Kawai M, Mizuno K, Takahashi S, Shirai T, Yamada-Namikawa C, Nakanishi M, Kajiyama H, Kikkawa F, Sugiura-Ogasawara M.
  • Journal Title: J Obstet Gynaecol Res. Volume: 40 Issue: 5 Pages: 197-204
  • DOI: 10.1111/jog.12324
  • Peer Reviewed
• [Journal Article] Mammalian-specific H2A variant, H2ABbd, is Involved in Apoptotic Induction via Activation of NF-κB Signaling Pathway. (2014)
  • Author(s): Goshima T, Shimada M, Sharif J, Matsuo H, Misaki T, Johmura Y, Murata K, Koseki H, Nakanishi M.
  • Journal Title: J Biol Chem. Volume: 未定 Issue: 17 Pages: 11656-66
  • DOI: 10.1074/jbc.m113.541664
  • Peer Reviewed
• [Presentation] DNA damage response and repair in cancer. (2016)
  • Author(s): Makoto Naknishi
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Cellular senescence as an anti-cancer barrier . (2016)
  • Author(s): Makoto Nakanishi
  • Organizer: Tenth Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: U.S.A. Hawaii
  • Year and Date: 2016-02-17
  • Int'l Joint Research / Invited
• [Presentation] ヒストンユビキチン化・脱ユビキチン化によるDNA維持メチル化制御 (2016)
  • Author(s): Makoto Nakanishi
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Cell Cycle Control in Disease (2016)
  • Author(s): Makoto Naknishi
  • Organizer: The Korean Society for Molecular and Cellular Biology(KSMCB)
  • Place of Presentation: COEX ソウル市 韓国
  • Int'l Joint Research / Invited
• [Presentation] Ubiquitylation/deubiquifylation circuit of histone H3 couples maintenace DNA methylation and DNA replication. (2015)
  • Author(s): Makoto Nakanishi
  • Organizer: CSHL Ubiquitin Family
  • Place of Presentation: U.S.A. CSH
  • Year and Date: 2015-04-24
  • Int'l Joint Research / Invited
• [Presentation] Necessary and sufficient role for a mitosis skip in senescence induction. (2014)
  • Author(s): 中西 真
  • Organizer: Fusion Conferences DNA Replication as a Source of DNA Damage
  • Place of Presentation: Jadida、モロッコ
  • Year and Date: 2014-09-30 – 2014-10-03
• [Presentation] A time lag between activations of 2 distinct DNA damage response determines senescence induction (2014)
  • Author(s): 中西 真
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: （横浜市）パシフィコ横浜
  • Year and Date: 2014-09-26
  • Invited
• [Presentation] Regulation of maintenance DNA methylation by ubiquitylation of histone H3 at lysine 23 (2014)
  • Author(s): 中西 真
  • Organizer: BENZON SYMPOSIUM No. 60 Nuclear regulation by ubiquitin
  • Place of Presentation: コペンハーゲン、デンマーク
  • Year and Date: 2014-08-18 – 2014-08-21
• [Presentation] Molecular mechanisms underlying induction of cellular senescence (2014)
  • Author(s): 中西 真
  • Organizer: 37th JSBG シンポジウム
  • Place of Presentation: （愛知県大府市）長寿研
  • Year and Date: 2014-06-26
  • Invited
• [Presentation] Regulation of maintenance DNA methylaton by histone H3 ubiquitylation (2014)
  • Author(s): 中西 真
  • Organizer: 2014KSBMB Annual Meeting
  • Place of Presentation: 韓国ソウル
  • Year and Date: 2014-05-15
  • Invited
• [Presentation] Molecular coupling between DNA replication and maintenance DNA methylation (2014)
  • Author(s): 中西 真
  • Organizer: IIAS conference 2014
  • Place of Presentation: （京都市）木津川国際高等研究所
  • Year and Date: 2014-05-13
  • Invited
• [Remarks] 東大医科研癌防御シグナル分野 研究業績
  • URL: http://www.ims.u-tokyo.ac.jp/cancer-cell-biology/type1/research1.html
• [Remarks] 東京大学医科学研究所癌防御シグナル分野ホームページ
  • URL: http://www.ims.u-tokyo.ac.jp/cancer-cell-biology/type1/index.html