Investigating mRNA methyl cap regulation, function and therapeutic potential

研究 mRNA 甲基帽调节、功能和治疗潜力

• 批准号: MR/K024213/1
• 负责人: Victoria Cowling
• 金额: $ 312.4万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK024213%2F1
• 关键词: Investigating; mRNA; methyl; cap; regulation

Victoria Cowling's lab at the University of Dundee investigate how proteins are made in human cells, with the aim of uncovering new approaches to stop the growth of cancer cells and parasites. The human body is made up of trillions of cells with many different functions, e.g. skin, muscle, gut cells. Our health is dependent on these cells responding rapidly to the "instructions" they receive from the body on how to function and whether to grow and multiply, rest or die. In this way, trillions of cells can co-ordinate their activities to form the human body. In cancer, our cells become less responsive to these instructions, and grow and divide in an uncontrolled manner. As a result masses of cells accumulate, often forming cancerous tumours. Cancer researchers investigate why cancer cells become unresponsive to instructions from the body, with the aim of developing new therapies to stop cancer cells growing. Cells are built from proteins and therefore for cells to grow and divide, new proteins need to be made. DNA found in our genes holds the "recipe" for making proteins, but it uses a messenger called RNA to provide precise instructions for proteins. Victoria Cowling's lab is investigating how the RNA messenger is made and handled in the cell, and how it is read to make proteins. Specifically, the Cowling group investigates a structure called the "methyl cap" which flags certain RNAs to be used to make proteins. They discovered that the methyl cap can be influenced by cancer-causing oncogenes and that it is needed for a certain oncogenes to function. Encouraged by these initial results, the Cowling group has initiated a programme of research investigating how the methyl cap is synthesized and regulated in the cell, and how this process goes wrong in cancer cells. They are also collaborating with the Dundee Drug discovery unit to use cutting-edge technology to look for new chemical compounds that stop the methyl cap from forming. Such compounds may form the starting point for developing new anti-cancer therapies. Since human parasites are also dependent on the methyl cap to make protein, Dr Cowling is collaborating with Prof Mike Ferguson at the University of Dundee, to investigate targeting the methyl cap in the parasite, T. brucei, which causes African Sleeping Sickness, a debilitating disease for which treatment remains limited.

维多利亚考林在邓迪大学的实验室研究蛋白质是如何在人类细胞中产生的，目的是发现阻止癌细胞和寄生虫生长的新方法。人体由数万亿个具有许多不同功能的细胞组成，例如皮肤，肌肉，肠道细胞。我们的健康依赖于这些细胞对它们从身体收到的关于如何运作以及是否生长和繁殖、休息或死亡的“指令”做出快速反应。通过这种方式，数万亿个细胞可以协调它们的活动来形成人体。在癌症中，我们的细胞对这些指令的反应变得不那么灵敏，并且以不受控制的方式生长和分裂。结果是大量的细胞聚集，经常形成癌性肿瘤。癌症研究人员正在研究为什么癌细胞对身体的指令没有反应，目的是开发新的疗法来阻止癌细胞的生长。细胞是由蛋白质组成的，因此细胞要生长和分裂，就需要制造新的蛋白质。在我们的基因中发现的DNA拥有制造蛋白质的“配方”，但它使用一种称为RNA的信使为蛋白质提供精确的指令。维多利亚考林的实验室正在研究RNA信使是如何在细胞中制造和处理的，以及它是如何被读取以制造蛋白质的。具体来说，考林小组研究了一种称为“甲基帽”的结构，它标志着某些RNA被用来制造蛋白质。他们发现甲基帽可以受到致癌基因的影响，并且它是某些致癌基因发挥作用所必需的。在这些初步结果的鼓舞下，Cowling小组启动了一项研究计划，调查甲基帽在细胞中是如何合成和调节的，以及这一过程在癌细胞中是如何出错的。他们还与邓迪药物发现部门合作，利用尖端技术寻找阻止甲基帽形成的新化合物。这些化合物可能成为开发新抗癌疗法的起点。由于人类寄生虫也依赖甲基帽来制造蛋白质，考林博士正在与邓迪大学的迈克·弗格森教授合作，研究靶向寄生虫T中的甲基帽。布鲁氏杆菌，引起非洲睡眠病，这是一种使人衰弱的疾病，治疗仍然有限。

项目成果

A novel RNA pol II CTD interaction site on the mRNA capping enzyme is essential for its allosteric activation.

• DOI: 10.1093/nar/gkab130
• 发表时间: 2021-04-06
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Bage MG;Almohammed R;Cowling VH;Pisliakov AV
• 通讯作者: Pisliakov AV

Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis.

• DOI: 10.1038/onc.2013.338
• 发表时间: 2014-07-03
• 期刊: Oncogene
• 影响因子: 8

Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: Insights from accelerated molecular dynamics simulations

RAM 变构激活人类 mRNA 帽甲基转移酶 (RNMT) 的机制：加速分子动力学模拟的见解

• DOI: 10.1101/558502
• 发表时间: 2019
• 作者: Bueren-Calabuig J

CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription.

• DOI: 10.1016/j.molcel.2016.02.008
• 发表时间: 2016-03-03
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Aregger M;Kaskar A;Varshney D;Fernandez-Sanchez ME;Inesta-Vaquera FA;Weidlich S;Cowling VH
• 通讯作者: Cowling VH

Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase

• DOI: 10.1101/2021.04.07.438810
• 发表时间: 2021-04
• 期刊: bioRxiv
• 作者: Souradeep Basu;Tiffany Mak;Rachel Ulferts;Mary Y. Wu;T. Deegan;R. Fujisawa;K. Tan;Chew Theng Lim;Clovis Basier;Berta Canal;Joseph F. Curran;L. Drury;Allison W. McClure;Emma L. Roberts;Florian Weissmann;Theresa U. Zeisner;R. Beale;V. Cowling;M. Howell;K. Labib;J. Diffley