Molecular mechanisms for pre-replication complexes assembly and its implication in chromosomal stability in mammalian cells

复制前复合物组装的分子机制及其对哺乳动物细胞染色体稳定性的影响

• 批准号: 17080013
• 负责人: FUJITA Masatoshi
• 金额: $ 74.24万
• 依托单位: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17080013/
• 关键词: 染色体DNA複製; 細胞周期; クロマチン; 染色体安定性; 細胞周期制御; Cdt1; SNF2H; クロマチンリモデリング; CRL4ユビキチンリガーゼ; CDC6; ATR; 複製チェックポイント; ORC; タンパク質分解制御; テロメア; 染色体不安定性; TRF2; 分子生物学; ゲノム; 遺伝子; 染色体; DNA複製

Chromosomal DNA, an essential genetic element, should be precisely replicated during cell growth, failure of which leads to cell death or cancer development. In this research project, we have clarified molecular mechanisms by which DNA replicates once and only once during cells dividing into two daughter cells. Especially, we found that Cdt1 protein is strictly regulated by multiple mechanisms, which are essential for precise DNA replication. Base on these findings, we think that Cdt1 would be a novel target of anti-cancer drugs and we are now trying to find out such compounds. In addition, it turned out that such mechanisms for DNA replication also contribute to maintenance of other chromosomal functions.

染色体DNA是一种必不可少的遗传元素，应在细胞生长过程中精确复制，其失败导致细胞死亡或癌症发育。在该研究项目中，我们阐明了分子机制，在分为两个子细胞的细胞中，DNA一次和仅一次复制一次。特别是，我们发现CDT1蛋白受到多种机制的严格调节，这对于精确的DNA复制至关重要。基于这些发现，我们认为CDT1将是抗癌药物的新靶标，我们现在正在尝试找出此类化合物。此外，事实证明，这种DNA复制机制也有助于维持其他染色体功能。

项目成果

Chromatin-modifying proteins that bind to Cdt1 and promote pre-RC formation

与 Cdt1 结合并促进前 RC 形成的染色质修饰蛋白

• 发表时间: 2008
• 作者: Sugimoto N;Waga S;Kiyono T;Fujita;M.;藤田雅俊;Nozomi Sugimoto
• 通讯作者: Nozomi Sugimoto

蛋白質核酸酵素(正井久雄、升方久夫、釣本敏樹、仁木宏典、篠原彰編集, 染色体動態制御における複製開始複合体因子の新たな機能, 増刊号「染色体サイクル」)

蛋白质核酸酶（由Hisao Masai、Hisao Masukata、Toshiki Tsurimoto、Hironori Niki和Akira Shinohara编辑，复制起始复合体因子在调节染色体动力学中的新功能，特刊“染色体循环”）

• 发表时间: 2009
• 作者: Tatsumi Y;Ezura K;Yoshida K;Kiyono T;Ohta S;Obuse C;Fujita;M.;Yasutoshi Tatsumi;Nozomi Sugimoto;藤田雅俊.
• 通讯作者: 藤田雅俊.

現所属、九州大学・大学院薬学研究院ホームページ

现所属九州大学药学研究科主页

Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.

细胞周期蛋白 A 依赖性激酶对 Cdt1 的磷酸化可负向调节其功能，但不影响 Geminin 结合。

• 发表时间: 2004
• 期刊: J. B i o l. C h e m. 279
• 作者: Sugimoto N;Tatsumi Y;Tsurumi T;Matsukage A;Kiyono T;Nishitani H;Fujita M.
• 通讯作者: Fujita M.

Cyclin A-Cdk1 regulates the origin firing program in mammalian cells

• DOI: 10.1073/pnas.0809350106
• 发表时间: 2009-03-03
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Katsuno, Yuko;Suzuki, Ayumi;Nakanishi, Makoto
• 通讯作者: Nakanishi, Makoto