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Nozomi Sugimoto Last modified date:2022.01.28

Assistant Professor / Department of Chemo-Pharmaceutical Sciences
Department of Pharmaceutical Health Care and Sciences
Faculty of Pharmaceutical Sciences


Graduate School
Undergraduate School


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Homepage
https://kyushu-u.pure.elsevier.com/en/persons/nozomi-sugimoto
 Reseacher Profiling Tool Kyushu University Pure
Phone
092-642-6637
Fax
092-642-6635
Academic Degree
Ph.D.
Country of degree conferring institution (Overseas)
No
Field of Specialization
Molecular biology
Total Priod of education and research career in the foreign country
00years00months
Research
Research Interests
  • Comprehensive analysis of mechanisms for p53 regulation by novel oncogene GRWD1
    keyword : GRWD1, p53, MDM2, RPs
    2018.04.
  • Novel histone chaperone GRWD1 may suppresses p53 and be involved in carcinogenesis.
    keyword : GRWD1, p53, MDM2, RP, Pura
    2015.04.
  • Elucidation of GRWD1 functions for transcription by identification of the novel binding proteins
    keyword : GRWD1, Pura, p53, transcription, next-generation sequencing
    2013.04.
  • Elucidation on promotion of the replication licensing by the Cdt1 binding chromatin regulating factor
    keyword : Cdt1, DNA replication, MCM, SNF2H, GRWD1
    2009.04.
  • Elucidation of the function and regulation mechanisms of the replication licensing factor Cdt1 in human cells
    keyword : Cdt1, replication、MCM
    2003.04.
Academic Activities
Books
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.
Reports
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.
Papers
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, 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, 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, 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.
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, 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.
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.
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.
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.
Presentations
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. 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.
4. 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.
5. 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.
6. 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.
7. 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.