Elucidation of the regulatory mechanisms of aging using senescence-accerelation mice

• Project/Area Number: 16K15239
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Nakanishi Makoto 東京大学, 医科学研究所, 教授 (40217774)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 細胞老化 / 加齢性変化 / 寿命 / 発がん / 遺伝子改変マウス / 大腸発がん / がん抑制 / 分子病態学

Outline of Final Research Achievements

In order to clarify whether acceleration of cellular senescence enhances age-related changes in vivo and shorten the lifespan, we generated senescence acceleration mice using non-degradation mutant of Claspin. Mouse embryonic fibroblasts from transgenic mice harboring non-degradation mutant of Claspin (Senescence acceleration mice) showed a significant higher sensitivity to senescence upon low level of genome stresses than those from wild-type mice. Interestingly, the senescence acceleration mice exhibited acceleration of some age-associated phenotypes such as emaciation, lordokyphosis, and inactive. These results thus suggest that high senescence sensitivity accelerates aging phenotypes in vivo.

Research Products

• [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] Structure of the Dnmt1 Reader Module Complexed with a Unique Two-Mono-Ubiquitin Mark on Histone H3 Reveals the Basis for DNA Methylation Maintenance. (2017)
  • Author(s): Ishiyama, S., Nishiyama, A., Saeki, Y., Moritsugu, K., Morimoto, D., Yamaguchi, L., Arai, N., Matsumura, R., Kawakami, T., Mishima, Y., Hojo, H., Shimamura, S., Ishikawa, F., Tajima, S., Tanaka, K., Ariyoshi, M., Shirakawa, M., Ikeguchi, M., Kidera, A., Suetake, I., Arita, K. and Nakanishi M.
  • Journal Title: Mol Cell Volume: 68 Pages: 350-360
  • Peer Reviewed / Open Access
• [Journal Article] Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking-independent lung adenocarcinoma. (2017)
  • Author(s): Suzuki, A., Okuda, K., Yano, M., Oda, R., Sakane, T., Kawano, O., Haneda, H., Moriyama, S., Nakanishi, M. and Nakanishi, R.
  • Journal Title: Oncol Lett Volume: 14 Issue: 1 Pages: 891-898
  • DOI: 10.3892/ol.2017.6216
  • Peer Reviewed / Open Access
• [Journal Article] The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy. (2017)
  • Author(s): Iwata T, Uchino T, Koyama A, Johmura Y, Koyama K, Saito T, Ishiguro S, Arikawa T, Komatsu S, Miyachi M, Sano T, Nakanishi M, Shimada M.
  • Journal Title: Plos one Volume: 12 Issue: 5 Pages: 1-13
  • DOI: 10.1371/journal.pone.0178221
  • 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
• [Presentation] Molecular coupling between DNA methylation maintenance and DNA replication. (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: L'Institut Curie
  • Int'l Joint Research / Invited
• [Presentation] Molecular coupling between DNA methylation maintenance and DNA replication. (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: University of Copenhagen
  • Int'l Joint Research / Invited
• [Presentation] Mechanism of senescence induction and maintenance and their role in aging (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: 東北大学研究推進・支援基地の創出センター/Aging Science: from Molecules to Society
  • Int'l Joint Research
• [Presentation] エピゲノム修飾を介したオートファジー制御とがん (2017)
  • Author(s): 中西 真
  • Organizer: がんシリーズ第６回 エピゲノム情報に基づくがんの制御
• [Presentation] 細胞老化と前立腺疾患 (2017)
  • Author(s): 中西 真
  • Organizer: 第２０回 UPTシンポジウム
• [Presentation] DNA damage response and repair in cancer. Essential role of auto-activation circuitry on Aurora B-mediated H2AX-pS121 in mitosis. (2016)
  • Author(s): Makoto Nakanishi
  • 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] 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 Nakanishi
  • 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
• [Book] 実験医学 2017年9月号 (2017)
  • Author(s): 城村 由和 中西 真
  • Total Pages: 6
  • Publisher: 羊土社
  • ISBN: 9784758101677