九州大学 研究者情報
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杉本 のぞみ(すぎもと のぞみ) データ更新日:2022.01.28

助教 /  薬学研究院 臨床薬学部門 医薬化学


主な研究テーマ
新規がん遺伝子GRWD1によるp53抑制機構の包括的解析
キーワード:GRWD1, p53, MDM2, RPs
2018.04.
新規ヒストンシャペロンGRWD1によるp53抑制と発がんへの関与
キーワード:GRWD1, p53, MDM2, RP, Pura
2015.04.
新規ヒストンシャペロンGRWD1の結合因子を介した転写制御機構の解明
キーワード:GRWD1, Pura, p53, 転写, 次世代シーケンサー
2013.04.
Cdt1結合性クロマチン制御因子によるライセンス化の促進に関する研究
キーワード:Cdt1、DNA複製、MCM、SNF2H、GRWD1
2009.04.
ヒト細胞における複製ライセンシング因子Cdt1の機能ならびに分解制御機構に関する研究
キーワード:Cdt1、DNA複製、MCM
2003.04.
研究業績
主要著書
1. Nozomi Sugimoto, Masatoshi Fujita, Molecular mechanism for chromatin regulation during MCM loading in mammalian cells., In: Masai H., Foiani M. (eds) DNA Replication. Advances in Experimental Medicine and Biology, Springer, 10.1007/978-981-10-6955-0_3, 2017.12, [URL].
主要原著論文
1. Hiroki Fujiyama, Takahiro Tsuji, Kensuke Hironaka, Kazumasa Yoshida, Nozomi Sugimoto (Corresponding author), Masatoshi Fujita, GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity., Journal of Biochemistry, doi.org/10.1093/jb/mvz075, 167, 1, 15-24, 2021年度JB論文賞受賞。, 2020.01, [URL], Glutamate-rich WD40 repeat containing 1 (GRWD1) functions as a histone chaperone to promote loading of the MCM replication helicase at replication origins. GRWD1 is overexpressed in several cancer cell lines, and GRWD1 overexpression confers tumorigenic potential in human cells. However, less is known concerning its oncogenic activity. Our previous analysis showed that GRWD1 negatively regulates the tumour suppressor p53 via the RPL11-MDM2-p53 and RPL23-MDM2-p53 axes. Here, we demonstrate that GRWD1 directly interacts with p53 via the p53 DNA-binding domain. Upon DNA damage, GRWD1 downregulation resulted in increased p21 expression. Conversely, GRWD1 co-expression suppressed several p53-regulated promoters. GRWD1 interacted with the p21 and MDM2 promoters, and these interactions required p53. By using the Human Cancer Genome Atlas database, we found that GRWD1 expression levels are inversely correlated with the expression levels of some p53-target genes. Interestingly, high GRWD1 expression in combination with low expression levels of some p53-target genes was significantly correlated with poor prognosis in skin melanoma patients with wild-type p53. Taken together, our findings suggest a novel oncogenic function of GRWD1 as a transcriptional regulator of p53 and that GRWD1 might be an attractive therapeutic target and prognostic marker in cancer therapy..
2. Nozomi Sugimoto (Corresponding author), Kazumitsu Maehara, Kazumasa Yoshida, Yasuyuki Ohkawa, Masatoshi Fujita, Genome-wide analysis of the spatiotemporal regulation of firing and dormant origins in human cells., Nucleic Acids Research, 10.1093/nar/gky476, 2018.06, [URL], In metazoan cells, only a limited number of mini chromosome maintenance (MCM) complexes are fired during S phase, while the majority remain dormant. Several methods have been used to map replication origins, but such methods cannot identify dormant origins. Herein, we determined MCM7-binding sites in human cells using ChIP-Seq, classified them into firing and dormant origins using origin data and analysed their association with various chromatin signatures. Firing origins, but not dormant origins, were well correlated with open chromatin regions and were enriched upstream of transcription start sites (TSSs) of transcribed genes. Aggregation plots of MCM7 signals revealed minimal difference in the efficacy of MCM loading between firing and dormant origins. We also analysed common fragile sites (CFSs) and found a low density of origins at these sites. Nevertheless, firing origins were enriched upstream of the TSSs. Based on the results, we propose a model in which excessive MCMs are actively loaded in a genome-wide manner, irrespective of chromatin status, but only a fraction are passively fired in chromatin areas with an accessible open structure, such as regions upstream of TSSs of transcribed genes. This plasticity in the specification of replication origins may minimize collisions between replication and transcription..
3. Shinya Watanabe, Hiroki Fujiyama, Takuya Takafuji, Kota Kayama, Masaki Matsumoto, Keiichi I Nakayama, Kazumasa Yoshida, Nozomi Sugimoto (Corresponding author), Masatoshi Fujita, Glutamate-rich WD40 repeat containing 1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system, Journal of Cell Science, 10.1242/jcs.213009, 131, 2018.08, Glutamate-rich WD40 repeat-containing 1 (GRWD1) is a Cdt1-binding protein that promotes mini-chromosome maintenance (MCM) loading through its histone chaperone activity. GRWD1 acts as a tumor-promoting factor by downregulating p53 (also known as TP53) via the RPL11-MDM2-p53 axis. Here, we identified GRWD1-interacting proteins using a proteomics approach and showed that GRWD1 interacts with various proteins involved in transcription, translation, DNA replication and repair, chromatin organization, and ubiquitin-mediated proteolysis. We focused on the ribosomal protein ribosomal protein L23 (RPL23), which positively regulates nucleolar stress responses through MDM2 binding and inhibition, thereby functioning as a tumor suppressor. Overexpression of GRWD1 decreased RPL23 protein levels and stability; this effect was restored upon treatment with the proteasome inhibitor MG132. EDD (also known as UBR5), an E3 ubiquitin ligase that interacts with GRWD1, also downregulated RPL23, and the decrease was further enhanced by co-expression of GRWD1. Conversely, siRNA-mediated GRWD1 knockdown upregulated RPL23. Co-expression of GRWD1 and EDD promoted RPL23 ubiquitylation. These data suggest that GRWD1 acts together with EDD to negatively regulate RPL23 via the ubiquitin-proteasome system. GRWD1 expression reversed the RPL23-mediated inhibition of anchorage-independent growth in cancer cells. Our data suggest that GRWD1-induced RPL23 proteolysis plays a role in downregulation of p53 and tumorigenesis..
4. Kota Kayama, Shinya Watanabe, Takuya Takafuji, Takahiro Tsuji, Kensuke Hironaka, Masaki Matsumoto, Keiichi Nakayama, Masato Enari, Takashi Kohno, Kouya Shiraishi, Tohru Kiyono, Kazumasa Yoshida, Nozomi Sugimoto, Masatoshi Fujita, GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis, EMBO Report, 10.15252/embr.201642444, 18, 123-137, 2017.01, [URL], The ribosomal protein L11 (RPL11) binds and inhibits the MDM2 ubiquitin ligase, thereby promoting p53 stability. Thus, RPL11 acts as a tumor suppressor. Here, we show that GRWD1 (glutamate-rich WD40 repeat containing 1) physically and functionally interacts with RPL11. GRWD1 is localized to nucleoli and is released into the nucleoplasm upon nucleolar stress. Silencing of GRWD1 increases p53 induction by nucleolar stress, whereas overexpression of GRWD1 reduces p53 induction. Furthermore, GRWD1 overexpression competitively inhibits the RPL11-MDM2 interaction and alleviates RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53. These effects are mediated by the N-terminal region of GRWD1, including the acidic domain. Finally, we show that GRWD1 overexpression in combination with HPV16 E7 and activated KRAS confers anchorage-independent growth and tumorigenic capacity on normal human fibroblasts. Consistent with this, GRWD1 overexpression is associated with poor prognosis in cancer patients. Taken together, our results suggest that GRWD1 is a novel negative regulator of p53 and a potential oncogene..
5. Masahiro Aizawa, Nozomi Sugimoto, Shinya Watanabe, Kazumasa Yoshida, Masatoshi Fujita, Nucleosome assembly and disassembly activity of GRWD1, a novel Cdt1-binding protein that promotes pre-replication complex formation., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 10.1016/j.bbamcr.2016.08.008, 2016.08, [URL].
6. Nozomi Sugimoto, Kazumitsu Maehara, Kazumasa Yoshida, Shuhei Yasukouchi, Satoko Osano, Shinya Watanabe, Masahiro Aizawa, Takashi Yugawa, Tohru Kiyono, Hitoshi Kurumizaka, Yasuyuki Ohkawa, Masatoshi Fujita, Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture, Nucleic Acids Research, 10.1093/nar/gkv509, 2015.07, [URL], Efficient pre-replication complex (pre-RC) formation on chromatin templates is crucial for the maintenance of genome integrity. However, the regulation of chromatin dynamics during this process has remained elusive. We found that a conserved protein, GRWD1 (glutamate-rich WD40 repeat containing 1), binds to two representative replication origins specifically during G1 phase in a CDC6- and Cdt1-dependent manner, and that depletion of GRWD1 reduces loading of MCM but not CDC6 and Cdt1. Furthermore, chromatin immunoprecipitation coupled with high-throughput sequencing (Seq) revealed significant genome-wide co-localization of GRWD1 with CDC6. We found that GRWD1 has histone-binding activity. To investigate the effect of GRWD1 on chromatin architecture, we used formaldehyde-assisted isolation of regulatory elements (FAIRE)-seq or FAIRE-quantitative PCR analyses, and the results suggest that GRWD1 regulates chromatin openness at specific chromatin locations. Taken together, these findings suggest that GRWD1 may be a novel histone-binding protein that regulates chromatin dynamics and MCM loading at replication origins..
7. Nozomi Sugimoto, Takashi Yugawa, Masayoshi Iizuka, Tohru Kiyono, Masatoshi Fujita, Chromatin remodeler sucrose nonfermenting 2 homolog (SNF2H) is recruited onto DNA replication origins through interaction with Cdc10 protein-dependent transcript 1 (Cdt1) and promotes pre-replication complex formation, J. Biol. Chem., 10.1074/jbc.M111.256123, 286, 45, 39200-39210, 2011.11, [URL].
8. Sugimoto, N., Yoshida, K., Tatsumi, Y., Yugawa T., Narisawa-Saito, M., Waga, S., Kiyono, T. and Fujita, M, Redundant and differential regulation of multiple licensing factor ensures prevention of re-replication in normal human cells, J. Cell Sci., 10.1242/jcs.01889, 122, 1184-1191, 2009.04, [URL].
9. Sugimoto, N., Kitabayashi, I., Osano, S., Tatsumi, Y., Yugawa, T., Narisawa-Saito, M., Matsukage, A., Kiyono, T. and Fujita, M, Identification of novel human Cdt1-binding proteins by a proteomics approach: proteolytic regulation by APC/C-Cdh1, Mol. Biol. Cell, 10.1091/mbc.E07-09-0859, 19, 3, 1007-1021, 2008.03, [URL].
10. Tatsumi, Y., Sugimoto, N., Yugawa, T., Narisawa-Saito, M., Kiyono, T., Fujita, M., Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability, J. Cell Sci., 10.1242/jcs.03031, 119, 3128-3140, 2006.08.
11. Nishitani, H., Sugimoto, N., Roukos, V., Nakanishi, Y., Saijo, M., Obuse, C., Tsurimoto, T., Nakayama, K., Nakayama, K., Fujita, M., Lygerou, Z. and Nishimoto, T, Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis, EMBO J., 10.1038/sj.emboj.7601002, 25, 1126-1136, 2006.03.
12. Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H. and Fujita, M, Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding, J. Biol. Chem., 10.1074/jbc.M313175200, 279, 19, 19691-19697, 2004.05.
主要総説, 論評, 解説, 書評, 報告書等
1. Takuya Takafuji, Kota, Kayama, Nozomi, Sugimoto, Masatoshi Fujita, GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins., Cell Cycle, 10.1080/15384101.2017.1338987, 2017.08, [URL].
主要学会発表等
1. Nozomi Sugimoto, Nari Fujita, Saki Tsujita, Takuto Iwamura, Kazumitsu Maehara, Kazumasa Yoshida, Yasuyuki Ohkawa, Masatoshi Fujita, Systematic elucidation of mechanisms underlying formation of licensed chromatin in human cells., 第42回日本分子生物学会年会 (招待講演), 2019.12, One of the fundamental events in the cell cycle is complete and precise duplication of the genome. To initiate DNA replication, it is essential to form pre-replication complexes (pre-RCs). During late mitosis to G1 phase, the ORC, CDC6, Cdt1 and MCM2-7 proteins are sequentially assembled on chromatin. It is thought that chromatin structure negatively impacts MCM loading. In human cells, three Cdt1-binding chromatin-handling factors, histone acetyl transferase HBO1, ATP-dependent chromatin remodeler WICH (the heterodimer of SNF2H-WSTF), and novel histone chaperone GRWD1, are recruited to chromatin and facilitates MCM loading. However, the precise molecular mechanism(s) has remained elusive. For example, it is unclear how they function cooperatively in the promotion of MCM loading. To gain further insight into the potential interplay among three chromatin-handling factors, we have tried to genome-widely understand their functions for nucleosome density, positioning, and histone modification at the licensed region. A result of this approach suggests that SNF2H co-localizes with pre-RC genome-wide and WICH may function to reduce nucleosome density at pre-RC sites. On the other hand, we have also used an in vitro reconstitution system to elucidate the mechanism(s). In this presentation, we will present and discuss our latest findings for the regulation of chromatin licensing..
2. Nozomi Sugimoto, Nari Fujita, Saki Tsujita, Takuto Iwamura, Kazumitsu Maehara, Kazumasa Yoshida, Yasuyuki Ohkawa, Masatoshi Fujita, Elucidation of mechanisms underlying formation of licensed chromatin in human cells., 第92回日本生化学会大会シンポジウム (招待講演), 2019.09, Efficient pre-replication complex (pre-RC) formation on chromatin templates is crucial for the maintenance of genome integrity. In human cells, three chromatin-handling factors, histone acetyl transferase HBO1, ATP-dependent chromatin remodeler SNF2H, and novel histone chaperone GRWD1, are recruited to chromatin and facilitates MCM loading. However, the precise mechanism(s) of this process has remained elusive. For example, it is not unclear how they function cooperatively in the promotion of MCM loading. To gain further insight into the potential interplay among three chromatin-handling factors and their functions in cells, we have tried to integrate their genome-wide binding profiles, the licensing region, nucleosome density and positioning, and histone modification. Furthermore, we have used an in vitro reconstitution system to elucidate the mechanism. In our presentation, we will share the latest findings for the regulation of chromatin licensing..
3. 杉本 のぞみ, 藤山拓己, 高藤拓哉, 中山敬一, 清野透, 吉田 和真, 藤田 雅俊, Molecular mechanisms by which GRWD1 down regulates p53 to transform cells., 第77回日本癌学会学術総会, 2018.09.
4. 杉本 のぞみ, 吉田 和真, 前原 一満, 大川 恭行, 藤田 雅俊, ヒト細胞におけるfiringおよびdormant originの時空間的制御のゲノムワイド解析, 第40回日本分子生物学会年会, 2017.12.
5. 杉本 のぞみ, 會澤 誠大, 吉田 和真, 前原 一満, 大川 恭行, 藤田 雅俊, Genome-wide analysis for spatiotemporal regulation of the pre-RC formation and firing in human cells, BMB2015, 2015.12.
6. Nozomi Sugimoto, Masahiro Aizawa, Kazumasa Yoshida, Kazumitsu Maehara, Yasuyuki Ohkawa, Masatoshi Fujita, Genome-scale analysis for spatiotemporal regulation of the pre-RC formation and firing in human cells, International Symposium on Non-Coding DNA and Chromosomal Integrity, 2015.08.
7. Nozomi Sugimoto, Kazumasa Yoshida, Kazumitsu Maehara, Yasuyuki Ohkawa, Fujita, M., Genome-wide analysis for spatiotemporal regulation of the pre-RC formation and firing in human cells, Eukaryotic DNA replication & Genome maintenance on Cold Spring Harbor Laboratory Meeting, 2015.09.
8. 杉本 のぞみ, 前原 一満, 吉田 和真, 安河内 周平, 渡邉 心也, 會澤 誠大, 清野 透, 胡桃坂 仁志, 大川 恭行, 藤田 雅俊, 新規ヒストンシャペロンGRWD1はゲノムワイドにクロマチン制御を行 い複製ライセンシングを促進する, 第37回日本分子生物学会年会 (招待講演), 2014.11.
9. Nozomi Sugimoto, Kazumitsu Maehara, Kazumasa Yoshida, Shuhei Yasukouchi, Shinya Watanabe, Masahiro Aizawa, Tohru Kiyono, Hitoshi Kurumizaka, Yasuyuki Ohkawa, Fujita, M., Genome-wide relationship between pre-replication complex formation and chromatin status., The 9th 3R Symposium, 2014.11.
10. 杉本 のぞみ, 前原 一満, 安河内 周平, 吉田 和真, 清野 透, 胡桃坂 仁志, 大川 恭行, 藤田 雅俊, Cdt1結合蛋白質GRWD1は新規ヒストンシャペロンでありクロマチン構造とMCM結合を制御している, 第36回日本分子生物学会年会・ワークショップ (招待講演), 2013.12.
11. 杉本 のぞみ, 前原 一満, 渡邉 心也, 清野 透, 胡桃坂 仁志, 大川 恭行, 藤田 雅俊, Cdt1結合蛋白質GRWD1はクロマチン構造および MCMローディングを制御する新規ヒストンシャペロンである, 第22回DNA複製・組換え・修復ワークショップ, 2013.11.
12. Nozomi Sugimoto, Kazumitsu Maehara, Shuhei Yasukouchi, Shinya Watanabe, Tohru Kiyono, Hitoshi Kurumizaka, Yasuyuki Ohkawa, Fujita, M., Cdt1-binding protein GRWD1 is a novel histone chaperone that regulates chromatin structure and MCM loading, Cold Spring Harbor Laboratory Meeting on "Eukaryotic DNA replication & Genome Maintenance", 2013.09.
13. 杉本 のぞみ, 前原 一満, 清野 透, 胡桃坂 仁志, 大川 恭行, 藤田 雅俊, Cdt1結合蛋白質GRWD1はクロマチン構造およびMCMローディングを制御する新規ヒストンシャペロンである, 第65回細胞生物学会・シンポジウム (招待講演), 2013.06.
14. Nozomi Sugimoto, Shuhei Yasukouchi, Kazumitsu Maehara, Tohru Kiyono, Hitoshi Kurumizaka, Yasuyuki Ohkawa, Masatoshi Fujita, The Cdt1-binding protein GRWD1 is a novel histone chaperone involved in replication licensing and cell growth, 第35回日本分子生物学会年会・ワークショップ (招待講演), 2012.12.
15. 杉本 のぞみ, 温川恭至, 清野 透, 胡桃坂仁志, 藤田 雅俊, The Cdt1-binding protein GRWD1 is a novel histone chaperone involved in replication licensing and cell growth, 第71回日本癌学会学術総会, 2012.09.
16. Nozomi Sugimoto, Shuhei Yasukouchi, Shinya Watanabe, Tohru Kiyono, Hitoshi Kurumizaka, Masatoshi Fujita, The Cdt1-binding protein GRWD1 is a novel histone chaperone involved in replication licensing., 第34回日本分子生物学会年会ワークショップ招待講演, 2011.12.
17. Nozomi Sugimoto, Takashi Yugawa, Tohru Kiyono, and Masatoshi Fujita, A chromatin remodeler SNF2H promotes pre-RC formation via Cdt1 interaction., 第33回日本分子生物学会年会・第83回日本生化学会大会・合同大会, 2010.12.
学会活動
所属学会名
日本分子生物学会
日本癌学会
日本薬学会
学会大会・会議・シンポジウム等における役割
2018.11.17~2018.11.18, 第35回日本薬学会九州支部大会, 座長.
2016.11.30~2016.12.02, 第39回日本分子生物学会年会, ポスター座長.
2012.12.11~2012.12.14, 第35回日本分子生物学会年会, ワークショッププログラム委員.
2012.12.11~2012.12.14, 第35回日本分子生物学会年会, 座長.
2012.09.15~2012.09.16, 第11回次世代を担う若手バイオ・フォーラム2012, アドバイザー.
2011.10.25~2011.10.27, 第21回DNA複製・組換え・ゲノム安定性制御ワークショップ, 座長.
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2020年度      
受賞
JB論文賞, 日本生化学会, 2021.07.
研究奨励賞, 上原記念生命科学財団 , 2012.03.
成瀬仁蔵先生記念賞受賞, 日本女子大学, 2009.03.
森村豊明会奨励賞, 公益財団法人 森村豊明会, 2005.10.
日本女子大学 学業・研究奨励賞, 日本女子大学, 2005.04.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2018年度~2020年度, 基盤研究(C), 代表, 新規がん遺伝子GRWD1によるp53抑制機構の包括的解析.
2015年度~2016年度, 若手研究(B), 代表, 新規ヒストンシャペロンGRWD1のp53抑制と発がんへの関与.
2013年度~2014年度, 若手研究(B), 代表, 新規ヒストンシャペロンGRWD1によるPuraを介した転写制御機構の解明.
2009年度~2011年度, 特別研究員奨励費, 代表, 複製開始及び染色体分配制御に関与するヒストン結合蛋白質GRWD1の解析.
2006年度~2008年度, 特別研究員奨励費, 代表, Cdt1結合蛋白質の網羅的同定によるDNA複製の細胞周期制御機構の解明.
競争的資金(受託研究を含む)の採択状況
2019年度~2020年度, 公益財団法人新日本先進医療研究財団助成金, 代表, リボソーム病原因因子RPS17による新規がん抑制機構の解明.
2018年度~2019年度, 公益財団法人福岡県すこやか健康事業団 第53回がん研究助成金, 代表, リボソーム因子RPS17との結合を介したGRWD1による発がん機構の解明.
2018年度~2020年度, 公益財団法人内藤記念科学振興財団 第13回内藤記念女性研究者研究助成金, 代表, GRWD1によるp53依存的および非依存的発がん機構の解明.
2013年度~2014年度, 上原記念生命科学財団 研究奨励金, 代表, ヒストンシャペロンGRWD1の新機能解明.
学内資金・基金等への採択状況
2017年度~2017年度, 研究補助者雇用支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.
2016年度~2016年度, 出産・育児復帰者支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.
2016年度~2016年度, 研究補助者雇用支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.
2015年度~2015年度, 出産・育児復帰者支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.
2015年度~2015年度, 研究補助者雇用支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.
2014年度~2014年度, 『女性研究者養成システム』における出産・育児期支援, 代表, 新規ヒストンシャペロンGRWD1による統合的細胞増殖ネットワーク制御機構の解明.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。
 
 
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