Dissection of mRNA degradation pathways and anomalies associated with targeted disruption of CCR4-NOT deadenylase complex

剖析 mRNA 降解途径和与 CCR4-NOT 脱腺苷酶复合物靶向破坏相关的异常情况

• 批准号: 21229006
• 负责人: YAMAMOTO TADASHI
• 金额: $ 132.45万
• 依托单位: Okinawa Institute of Science and Technology Graduate University (2011-2013)The University of Tokyo (2009-2010)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009-05-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21229006/
• 关键词: mRNA代謝; mRNA分解; 遺伝子欠損マウス; 疾患モデル; CCR4-NOT複合体; 脱アデニル化反応; 3’UTR; poly(A)配列; デアデニレース; mRNA; 翻訳; AU-rich; AU-rich配列

We have studied the physiological roles of the CCR4-NOT deadenylase complex by generating mouse lines in which each gene encoding individual subunit of the CCR4-NOT complex is disrupted. Mice thus produced were analyzed pathologically and anatomically, and we so far found that those mice were either embryonic lethal or abnormal in tissue development or showed loss of regulation in immune system and/or energy metabolism. We, therefore, assumed that CCR4-NOT deficient mouse lines could be models of human diseases. We also analyzed the molecular mechanisms by which the CCR4-NOT complex recognizes and degrades poly(A) tail of its target mRNAs. We solved the crystal structures of oligo(dA)-interacting enzymatic subunits CNOT6L and CNOT7. We also found the enzymatic subunits can target poly(A) tail of specific mRNA species through their interaction with regulatory subunits such as CNOT1 and CNOT3 that can recognize specific sequences present at 3'UTR regions of particular mRNAs.

我们通过建立编码CCR4-NOT复合体的每个亚单位的基因被破坏的小鼠系来研究CCR4-NOT复合体的生理作用。对产生的小鼠进行了病理学和解剖学分析，到目前为止，我们发现这些小鼠要么是胚胎致死的，要么是组织发育异常的，要么表现出免疫系统和/或能量代谢的调节缺失。因此，我们假设CCR4非缺陷小鼠品系可能是人类疾病的模型。我们还分析了CCR4-NOT复合体识别和降解其靶mRNAs的Poly(A)尾巴的分子机制。我们解决了寡聚(Da)相互作用的酶亚基CNOT6L和Cnot7的晶体结构。我们还发现，这些酶亚基可以通过与CNOT1和CNOT3等调节亚基的相互作用来靶向特定mRNA物种的Poly(A)尾巴，这些调节亚基可以识别特定mRNAs的3‘UTR区的特定序列。

项目成果

NMDAR2B tyrosine phosphorylation is involved in thermal nociception

NMDAR2B 酪氨酸磷酸化参与热伤害感受

• DOI: 10.1016/j.neulet.2012.04.007
• 发表时间: 2012
• 期刊: Neurosci Lett
• 影响因子: 2.5
• 作者: Delawary M;Tezuka T;Yamamoto T. (9名)
• 通讯作者: Yamamoto T. (9名)

Structural Basis for the Antiproliferative Activity of the Tob-hCaf1 Complex

• DOI: 10.1074/jbc.m809250200
• 发表时间: 2009-05-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Horiuchi, Masataka;Takeuchi, Kosei;Inagaki, Fuyuhiko
• 通讯作者: Inagaki, Fuyuhiko

脱アデニル酵素CCR4-NOT複合体による肥満症制御

通过去腺苷酸酶 CCR4-NOT 复合物控制肥胖

• 发表时间: 2012
• 作者: 高橋明格;山本雅ら
• 通讯作者: 山本雅ら

The CCR4-NOT complex, a deadenylase that controla decay for specific sets of mRNAs in a context-dependent manner

CCR4-NOT 复合体，一种去腺苷酸酶，以上下文依赖性方式控制特定 mRNA 组的衰变

• 发表时间: 2011
• 作者: Chang;H.;et al.;Tadashi Yamamoto
• 通讯作者: Tadashi Yamamoto

肥満症発症におけるCCR4-NOT脱アデニル化酵素活性サブユニットの重要性

CCR4-NOT 去腺苷酸酶活性亚基在肥胖发展中的重要性

• 发表时间: 2013
• 作者: 高橋明格;山本雅ら
• 通讯作者: 山本雅ら