Mechanism analysis of progressive neurological abnormalities in xeroderma pigmentosum group A patients

• Project/Area Number: 26550042
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Nara Medical University
• Principal Investigator: Mori Toshio 奈良県立医科大学, 医学部, 研究教授 (10115280)
• Research Collaborator: Brooks P. J. ; Nakane Hironobu ; Hayashi Masaharu
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 色素性乾皮症 / 神経障害 / 酸化的DNA損傷 / サイクロプリン / モノクローナル抗体 / DNA修復異常 / 活性酸素 / ヌクレオチド除去修復 / 酵素標識免疫法

Outline of Final Research Achievements

Xeroderma pigmentosum group A (XP-A) patients develop progressive neurological abnormalities, which has been hypothesized to be associated with a type of oxidatively generated DNA damage called purine 8,5’-cyclo-2’-deoxynucleosides. Thus, we generated a monoclonal antibody specific for 8,5’-cyclo-2’-deoxynadenosine (Cyclo-dA) in DNA. The immunoassay revealed a linear dose-response between known amounts of Cyclo-dA in oligonucleotides and the antibody binding to them with a detection sensitivity of about 1 lesion/10<6> bases in a 1 ug DNA sample. We compared the amounts of Cyclo-dA accumulated in organs between wild type and XP-A mice with ages from 5 months to 29 months. We found that XP-A mice accumulate significantly higher amounts of Cyclo-dA in brains than do wild type mice, supporting the hypothesis.

Research Products

• [Journal Article] Targeted Inactivation of DNA Photolyase Genes in Medaka Fish (Oryzias latipes) (2017)
  • Author(s): Ishikawa-Fujiwara T, Shiraishi E, Fujikawa Y, Mori T, Tsujimura T, Todo T
  • Journal Title: Photochemistry and Photobiology Volume: 93 Issue: 1 Pages: 315-322
  • DOI: 10.1111/php.12658
  • Peer Reviewed / Open Access
• [Journal Article] Radiation-induced RhoGDIβ cleavage leads to perturbation of cell polarity: a possible link to cancer spreading (2016)
  • Author(s): Fujiwara, M., Okamoto, M., Hori, M., Suga, H., Jikihara, H., Sugihara, Y., Shimamoto, F., Mori, T., Nakaoji, K., Hamada, K., Ota, T., Wiedemuth, R., Temme, A., and Tatsuka, M.
  • Journal Title: J Cell Physiol Volume: 0 Issue: 11 Pages: 0-0
  • DOI: 10.1002/jcp.25362
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] In vivo spectrum of UVC-induced mutation in mouse skin epidermis may reflect the cytosine deamination propensity of cyclobutane pyrimidine dimers. (2015)
  • Author(s): H. Ikehata, T. Mori and M. Yamamoto
  • Journal Title: Photochem. Photobiol. Volume: 91 Issue: 6 Pages: 1488-1496
  • DOI: 10.1111/php.12525
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SUMOylation of xeroderma pigmentosum group C protein regulates DNA damage recognition during nucleotide excision repair (2015)
  • Author(s): Akita M
  • Journal Title: Sci. Rep. Volume: 5 Issue: 1 Pages: 10984-10984
  • DOI: 10.1038/srep10984
  • Peer Reviewed / Open Access
• [Journal Article] Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein. (2015)
  • Author(s): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thoma, Kaoru Sugasawa
  • Journal Title: Nucleic Acids Research Volume: 3 Issue: 3 Pages: 1700-1713
  • DOI: 10.1093/nar/gkv038
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative and in situ detection of oxidatively generated DNA damage 8,5’-cyclo-2’-deoxyadenosine using an immunoassay with a novel monoclonal antibody (2014)
  • Author(s): T. Iwamoto, P.J. Brooks, T. Nishiwaki, K. Nishimura, N. Kobayashi, S. Sugiura and T. Mori.
  • Journal Title: Photochem. Photobiol. Volume: xx Issue: 4 Pages: 829-836
  • DOI: 10.1111/php.12239
  • Peer Reviewed / Open Access
• [Presentation] 紫外線および酸化的DNA損傷に対するモノクローナル抗体の作製と応用 (2017)
  • Author(s): 森 俊雄
  • Organizer: 太陽紫外線防御研究員会第27回シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] 紫外線誘発DNA損傷に対するモノクローナル抗体 (2016)
  • Author(s): 森 俊雄
  • Organizer: 日本放射線影響学会第59回大会
  • Place of Presentation: 広島
  • Year and Date: 2016-10-26
  • Invited
• [Presentation] 酸化的DNA損傷サイクロプリン定量系の高感度化 (2016)
  • Author(s): 森 俊雄、岩本顕聡、杉浦重樹、中根裕信
  • Organizer: 第38回日本光医学・光生物学会
  • Place of Presentation: 京都
  • Year and Date: 2016-07-22
• [Presentation] DNA修復異常疾患（XP/CS/TTD）の病態と細胞/分子レベルの特性との関連 (2015)
  • Author(s): 森 俊雄
  • Organizer: 第37回日本光医学・光生物学会
  • Place of Presentation: 宮崎
  • Year and Date: 2015-07-17
• [Presentation] Quantitative detection of oxidative DNA damage 8,5’-cyclo-2’-deoxyadenosine using an immunoassay with a novel monoclonal antibody (2015)
  • Author(s): T. Mori, T. Iwamoto, P. J. Brooks, N. Kobayashi and S. Sugiura
  • Organizer: 15th International Congress of Radiation Research
  • Place of Presentation: Kyoto
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] 新規モノクローナル抗体を用いた酸化的DNA損傷サイクロプリンの定量測定と可視化 (2014)
  • Author(s): 森 俊雄、岩本顕聡、小林信彦、杉浦重樹
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Quantitative and in situ detection of oxidatively generated DNA damage 8,5’-cyclo-2’-deoxyadenosine using an immunoassay with a novel monoclonal antibody (2014)
  • Author(s): T. Iwamoto, P.J. Brooks, N. Kobayashi, S. Sugiura and T. Mori
  • Organizer: 16th International Congress on Photobiology
  • Place of Presentation: Cordoba, Argentina
  • Year and Date: 2014-09-08 – 2014-09-12
• [Presentation] 新規モノクローナル抗体を用いた酸化的DNA損傷サイクロプリンの定量測定と可視化 (2014)
  • Author(s): 岩本顕聡、P.J. Brooks、小林信彦、杉浦重樹、森 俊雄
  • Organizer: 第36回日本光医学・光生物学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-25 – 2014-07-26
• [Book] 4.2 ヒトにおけるヌクレオチド除去修復のしくみ、放射線医科学 -生体と放射線・電磁波・超音波- (2016)
  • Author(s): 森 俊雄
  • Total Pages: 189
  • Publisher: 医療科学社
• [Book] 光老化科学の最前線、第10章 DNA損傷の定量測定と可視化 (2015)
  • Author(s): 森 俊雄 (前田憲寿監修)
  • Total Pages: 301
  • Publisher: シーエムシー出版
• [Remarks] 奈良県立医科大学ラジオアイソトープ(RI)実験施設
  • URL: http://www.naramed-u.ac.jp/university/kenkyu-sangakukan/radioisotope/radioisotope.html