Mechanisms of degradation of human papillomavirus DNA helicase E1

• Project/Area Number: 26460564
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Kukimoto Iwao 国立感染症研究所, 病原体ゲノム解析研究センター, 室長 (70291127)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ヒトパピローマウイルス / 子宮頸癌 / ユビキチン / タンパク質分解 / ユビキチン化 / プロテアソーム / 蛋白質分解 / ウイルス複製

Outline of Final Research Achievements

Genome replication of human papillomavirus requires viral replicative DNA helicase E1, and regulation of intracellular E1 levels is important for controlling the virus life cycle. This study aimed to elucidate viral and cellular mechanisms of regulating E1 levels. We found that E1 was degraded in a manner dependent on its own ATPase activity, and that E1 was poly-ubiquitinated and degraded via the proteasome pathway. We further demonstrated that intracellular E1 levels were up-regulated with the treatment of tankyrase inhibitor XAV939, although the potential target of XAX939 for E1 up-regulation was not tankyrase but poly-ADP-ribose polymerase 1 (PARP1), suggesting that PARP1 is involved in negative regulation of E1 function.

Research Products

• [Journal Article] Within-Host Variations of Human Papillomavirus Reveal APOBEC-Signature Mutagenesis in the Viral Genome (2018)
  • Author(s): Hirose Yusuke、Onuki Mamiko、Tenjimbayashi Yuri、Mori Seiichiro、Ishii Yoshiyuki、Takeuchi Takamasa、Tasaka Nobutaka、Satoh Toyomi、Morisada Tohru、Iwata Takashi、Miyamoto Shingo、Matsumoto Koji、Sekizawa Akihiko、Kukimoto Iwao
  • Journal Title: Journal of Virology Volume: 印刷中 Issue: 12
  • DOI: 10.1128/jvi.00017-18
  • Peer Reviewed / Open Access
• [Journal Article] Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer (2017)
  • Author(s): Tenjimbayashi Yuri、Onuki Mamiko、Hirose Yusuke、Mori Seiichiro、Ishii Yoshiyuki、Takeuchi Takamasa、Tasaka Nobutaka、Satoh Toyomi、Morisada Tohru、Iwata Takashi、Miyamoto Shingo、Matsumoto Koji、Sekizawa Akihiko、Kukimoto Iwao
  • Journal Title: Infectious Agents and Cancer Volume: 12 Issue: 1 Pages: 44-44
  • DOI: 10.1186/s13027-017-0155-4
  • NAID: 120007128848
  • Peer Reviewed / Open Access
• [Journal Article] Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor. (2017)
  • Author(s): Mori S, Takeuchi T, Ishii Y, Yugawa T, Kiyono T, Nishina H, Kukimoto I.
  • Journal Title: Journal of Virology Volume: 91 Issue: 6
  • DOI: 10.1128/jvi.02413-16
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of methods using paraffin‐embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution (2016)
  • Author(s): Fujii T, Torii Y, Kukimoto I, Saito M, Iwata T, Takahashi H, Ichikawa R, Kawai S, Otani S, Aoki D
  • Journal Title: Cancer Sci Volume: 107(10) Issue: 10 Pages: 1520-1526
  • DOI: 10.1111/cas.13030
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic Variations of Human Papillomavirus Type 16: Implications for Cervical Carcinogenesis (2015)
  • Author(s): I. Kukimoto and M. Muramatsu.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 68 Issue: 3 Pages: 169-175
  • DOI: 10.7883/yoken.JJID.2014.584
  • NAID: 130005070792
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access
• [Journal Article] Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia. (2015)
  • Author(s): Kukimoto I, Mori S, Aoyama S, Wakae K, Muramatsu M, Kondo K.
  • Journal Title: Journal of Medical Virology Volume: 87 Issue: 10 Pages: 1754-1760
  • DOI: 10.1002/jmv.24215
  • Peer Reviewed
• [Journal Article] Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing. (2015)
  • Author(s): Wakae K, Aoyama S, Wang Z, Kitamura K, Liu G, Monjurul AM, Koura M, Imayasu M, Sakamoto N, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Kukimoto I, Yamaguchi K, Shigenobu S, Nishiyama T, Muramatsu M.
  • Journal Title: Virology Volume: 485 Pages: 460-466
  • DOI: 10.1016/j.virol.2015.08.017
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] APOBEC3A and 3C decrease human papillomavirus 16 pseudovirion infectivity. (2015)
  • Author(s): Ahasan MM, Wakae K, Wang Z, Kitamura K, Liu G, Koura M, Imayasu M, Sakamoto N, Hanaoka K, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Mori S, Kukimoto I, Muramatsu M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457 Issue: 3 Pages: 295-9
  • DOI: 10.1016/j.bbrc.2014.12.103
  • Peer Reviewed / Open Access
• [Journal Article] Identification of APOBEC3B promoter elements responsible for activation by human papillomavirus type 16 E6 (2015)
  • Author(s): Mori, S., T. Takeuchi, Y. Ishii, and I. Kukimoto.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 460 Issue: 3 Pages: 555-560
  • DOI: 10.1016/j.bbrc.2015.03.068
  • Peer Reviewed
• [Journal Article] Characterization of novel transcripts of human papillomavirus type 16 using CAGE technology (2015)
  • Author(s): Taguchi A, Nagasaka K, Kawana K, Hashimoto K, Kusumoto-Matsuo R, Plessy C, Miranda T, Nakamura H, Bonetti A, Oda K, Kukimoto I, Carninci P, Banks L, Osuga Y, Fujii T,
  • Journal Title: J Virol Volume: 89 Issue: 4 Pages: 2448-2452
  • DOI: 10.1128/jvi.03433-14
  • Peer Reviewed / Open Access
• [Journal Article] Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2/3 and invasive cervical cancer in Japanese women (2014)
  • Author(s): Azuma Y, Kusumoto-Matsuo R, Takeuchi F, Uenoyama A, Kondo K, Tsunoda H, Nagasaka K, Kawana K, Morisada T, Iwata T, Aoki D, Kukimoto I
  • Journal Title: Japan J Clin Oncol, Volume: 44(10) Issue: 10 Pages: 910-7
  • DOI: 10.1093/jjco/hyu112
  • Peer Reviewed / Open Access
• [Journal Article] HPVワクチン (2014)
  • Author(s): 柊元 巌
  • Journal Title: 臨床と微生物 Volume: 41 Pages: 725-729
• [Presentation] APOBEC変異導入を介したヒトパピローマウイルス発癌機構 (2018)
  • Author(s): 柊元 巌
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Detection of HPV L1 gene expression in cervical exfoliated cells from CIN patients by RT-PCR using consensus primers (2017)
  • Author(s): K. Kawana, A. Taguchi, K. Adachi, D. Maeda, S. Mori, I. Kukimoto, T. Iwata, A. and Mitsuhashi.
  • Organizer: 31st International Papillomavirus Conference
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2017-02-28
  • Int'l Joint Research
• [Presentation] Upregulation of APOBEC3B cytidine deaminase by HPV E6 and E7 via the TEAD transcription factor (2017)
  • Author(s): Kukimoto I, Tenjimbayashi Y, Hirose Y, Onuki M, Matsumoto K, Mori S.
  • Organizer: DNA tumour virus meeting
  • Int'l Joint Research
• [Presentation] Intra-patient variation of human papillomavirus genomes revealed by deep sequencing (2017)
  • Author(s): Hirose Y, Tenjimbayashi Y, Onuki M, Minaguchi T, Iwata T, Matsumoto K, Kukimoto I.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Whole-genome analysis of human papillomavirus 52 and 58 in Japanese women (2017)
  • Author(s): Tenjimbayashi Y, Hirose Y, Onuki M, Nakao S, Iwata T, Matsumoto K, Kukimoto I.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] MicroRNAs extracted from cervical mucus or exfoliated cells are promising biomarkers for cervical cancer screening (2017)
  • Author(s): Fujii T, Kukimoto I.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Whole-genome analysis of human papillomavirus 52/58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer (2017)
  • Author(s): Kukimoto I, Tenjimbayashi Y, Hirose Y, Onuki M, Iwata T, Matsumoto K.
  • Organizer: AOGIN 2017
  • Int'l Joint Research
• [Presentation] Whole-genome analysis of HPV52/58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer (2017)
  • Author(s): Kukimoto I, Tenjimbayashi Y, Hirose Y, Onuki M, Iwata T, Matsumoto K.
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Persistent expression of a broadly neutralizing monoclonal antibody against HPVs by AAV-mediated gene transfer (2017)
  • Author(s): Mori S, Kotani O, Takeuchi T, Ishii Y, Kukimoto I.
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Activation of human APOBEC3B promoter by HPV16 E6 through TEAD transcription factors (2016)
  • Author(s): S. Mori, T. Kiyono, H. Nishina, and I. Kukimoto.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-24
• [Presentation] TEAD-dependent, YAP/TAZ-independent activation of human APOBEC3B promoter by HPV16 E6 (2016)
  • Author(s): S. Mori, H. Nishina, and I. Kukimoto.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-07
• [Presentation] Estimation of HPV genotype attribution using cervical exfoliated cells for monitoring the efficacy of HPV vaccines (2016)
  • Author(s): T. Fujii, I. Kukimoto, T. Iwata, and D. Aoki.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-07
• [Presentation] Mechanism of multiple lysine 48-linked ubiquitin chain synthesis by E6AP (2016)
  • Author(s): Y. Masuda, Y. Saeki, S. Yanaka, H. Kawai, I. Kukimoto, K. Kato, K. Tanaka, C. Masutani.
  • Organizer: FASEB Science Research Conference, UBIQUITIN & CELLULAR REGULATION
  • Place of Presentation: Montana, U.S.A.
  • Year and Date: 2016-06-12
  • Int'l Joint Research
• [Presentation] HECTタイプユビキチンリガーゼによるK48ユビキチン鎖合成の分子機構 (2015)
  • Author(s): 増田雄司、柊元 巌、益谷央豪
  • Organizer: 第38回日本分子生物学会年会/第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] The L2 capsid protein of HPV16 promotes viral uncoating by inhibiting virus entry into the Golgi body through the L2-TRAPPC8 interaction (2015)
  • Author(s): Y. Ishii, S. Mori, T. Takeuchi, and I. Kukimoto.
  • Organizer: 第68回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-23
• [Presentation] Hypermutation in the E2 Gene of HPV16 in Cervical Intraepithelial Neoplasia (2015)
  • Author(s): I. Kukimoto, S. Mori, and K. Kondo.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] The significance of the existence of novel HPV16 derived antisense RNAs and the TSS-switch of HPV16 transcriptomes (2015)
  • Author(s): A. Taguchi, K. Nagasaka, K. Kawana, H. Nakamura, I. Kukimoto, K. Oda, and T. Fujii.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Mechanism of Lysine 48-linked Multiple Ubiquitin Chain Synthesis by an HECT Ubiquitin Ligase (2015)
  • Author(s): Y. Masuda, I. Kukimoto, C. Masutani
  • Organizer: EMBO Conference on Ubiquitin and ubiquitin-like modifiers: From molecular mechanisms to human diseases
  • Place of Presentation: Cavtat
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Presentation] Mechanisms of APOBEC3B Promoter Activation by HPV16 E6 (2015)
  • Author(s): S. Mori, T. Takeuchi, Y. Ishii, and I. Kukimoto.
  • Organizer: International Papillomavirus Conference
  • Place of Presentation: Lisbon
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] Hypermutation in the E2 Gene of HPV16 in Cervical Intraepithelial Neoplasia (2015)
  • Author(s): I. Kukimoto, K. Kondo, M. Muramatsu, and S. Mori.
  • Organizer: DNA Tumour Virus Meeting
  • Place of Presentation: Trieste
  • Year and Date: 2015-07-21
  • Int'l Joint Research
• [Presentation] ヒトパピローマウイルス16型E6/E7によるAPOBEC3Bプロモーターの活性化機構 (2014)
  • Author(s): 森 清一郎、竹内 隆正、石井 克幸、柊元 巌
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-12
• [Presentation] APOBEC3はHPV16 Pseudovirionの感染性を低下させる (2014)
  • Author(s): 若江 亨祥、Ahasan M Monjurul、王 哲、喜多村 晃一、森 清一郎、柊元 巌、中村 充弘、藤原 浩、村松 正道
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-12
• [Presentation] ヒトパピローマウイルス16型のがん蛋白質E6/E7によるAPOBEC3Bプロモーターの活性化 (2014)
  • Author(s): 森 清一郎、柊元 巌
  • Organizer: 第73回日本癌学会学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] 日本人女性のCIN2/3および子宮頸部浸潤癌でのHPV遺伝子型分布 (2014)
  • Author(s): 柊元 巌、近藤 一成、岩田 卓、川名 敬
  • Organizer: 第73回日本癌学会学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] Wee1 binds to and stabilizes the E1 helicase of human papillomavirus type 16 (2014)
  • Author(s): Kusumoto-Matsuo R, Mori S, Maehama T, Kukimoto I.
  • Organizer: 29th International Papillomavirus Conference
  • Place of Presentation: シアトル
  • Year and Date: 2014-08-25
• [Presentation] Characterization of novel transcripts of human papillomavirus type 16 and host interactions using CAGE technology (2014)
  • Author(s): Taguchi A, Nagasaka K, Kawana K, Hashimoto K, Kusumoto-Matsuo R, Kamoto H, Bonetti A, Kukimoto I, Carninci P, Banks L, Osuga Y, Fujii T.
  • Organizer: 29th International Papillomavirus Conference
  • Place of Presentation: シアトル
  • Year and Date: 2014-08-24
• [Remarks] 国立感染症研究所年報 平成２８年度
  • URL: https://www.niid.go.jp/niid/images/annual/h28/201620.pdf