Mechanistic determination of how microRNAs control gene-expression

microRNA 如何控制基因表达的机制测定

• 批准号: BB/N017005/2
• 负责人: Martin Bushell
• 金额: $ 43.14万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN017005%2F2
• 关键词: Mechanistic; determination; how; microRNAs; control

Recently, a completely new way of controlling gene expression has been discovered. This has come to light after the identification of a new class of genes, which unlike most genes do not produce proteins, but instead are processed into short RNA molecules called microRNAs. There are around 1000 different microRNAs within the human genome, all of which have different effects. They work by binding to the messenger RNA of protein encoding genes and inhibiting production of the protein encoded within the messenger RNA. Each of these 1000 small RNA molecules is believed to interact with and regulate around 200 protein encoding genes, thus adding to the complexity of the regulation of the human genome. Already it has become clear that malfunction of miRNA regulation is associated with virtually all human disease, including: cancer, diabetes, and viral infections. In 2002 Science magazine called miRNA the breakthrough of the year, and these small RNA molecules have been termed the "Dark Matter of the cell". MicroRNAs were only discovered in 2001 and, amazingly, already within this short period, microRNA-based drugs are in clinical trials for a number of human diseases demonstrating the usefulness of the research within this field. However, despite the rapid advances within this field, how these small RNA molecules exert their effects on protein production is currently unclear and controversial. As manipulation of these small RNA molecules is a realistic approach for the treatment of a number of human diseases, understanding how these therapeutic agents work will be critical for their development and safe use. This proposal aims to determine the mechanism by which these small RNA molecules control the production of proteins within the human body and to resolve the controversy within the field by supplying testable models which can be probed by many laboratories around the world.

最近，一种全新的控制基因表达的方法被发现。这是在发现了一类新的基因后发现的，与大多数基因不同，这类基因不产生蛋白质，而是被加工成称为microRNA的短RNA分子。人类基因组中大约有1000种不同的microRNA，它们都有不同的作用。它们通过与蛋白质编码基因的信使RNA结合并抑制信使RNA内编码的蛋白质的产生来起作用。这1000个小RNA分子中的每一个被认为与大约200个蛋白质编码基因相互作用并调节，从而增加了人类基因组调节的复杂性。现在已经很清楚，miRNA调控的功能障碍与几乎所有的人类疾病有关，包括：癌症、糖尿病和病毒感染。2002年，《科学》杂志将miRNA称为年度突破，这些小RNA分子被称为“细胞的暗物质”。microRNA直到2001年才被发现，令人惊讶的是，在这短短的时间内，基于microRNA的药物已经在许多人类疾病的临床试验中，证明了该领域研究的有用性。然而，尽管在这一领域取得了迅速的进展，这些小RNA分子如何发挥其对蛋白质生产的影响目前还不清楚和有争议的。由于操纵这些小RNA分子是治疗许多人类疾病的现实方法，因此了解这些治疗剂如何工作对于它们的开发和安全使用至关重要。该提案旨在确定这些小RNA分子控制人体内蛋白质产生的机制，并通过提供可由世界各地许多实验室探索的可测试模型来解决该领域的争议。

项目成果

Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization.

• DOI: 10.1186/s13059-021-02494-w
• 发表时间: 2021-10-06
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Gillen SL;Giacomelli C;Hodge K;Zanivan S;Bushell M;Wilczynska A
• 通讯作者: Wilczynska A

DDX17 is required for efficient DSB repair at DNA:RNA hybrid deficient loci.

• DOI: 10.1093/nar/gkac843
• 发表时间: 2022-10-14
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Bader, Aldo S.;Luessing, Janna;Hawley, Ben R.;Skalka, George L.;Lu, Wei-Ting;Lowndes, Noel F.;Bushell, Martin
• 通讯作者: Bushell, Martin

MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.

• DOI: 10.1158/2159-8290.cd-20-0652
• 发表时间: 2021-05
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Knight JRP;Alexandrou C;Skalka GL;Vlahov N;Pennel K;Officer L;Teodosio A;Kanellos G;Gay DM;May-Wilson S;Smith EM;Najumudeen AK;Gilroy K;Ridgway RA;Flanagan DJ;Smith RCL;McDonald L;MacKay C;Cheasty A;McArthur K;Stanway E;Leach JD;Jackstadt R;Waldron JA;Campbell AD;Vlachogiannis G;Valeri N;Haigis KM;Sonenberg N;Proud CG;Jones NP;Swarbrick ME;McKinnon HJ;Faller WJ;Le Quesne J;Edwards J;Willis AE;Bushell M;Sansom OJ
• 通讯作者: Sansom OJ

iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis.

• DOI: 10.1038/s41467-023-44167-1
• 发表时间: 2023-12-18
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bader, Aldo S.;Bushell, Martin
• 通讯作者: Bushell, Martin

Codon optimality in cancer.

• DOI: 10.1038/s41388-021-02022-x
• 发表时间: 2021-11
• 期刊: Oncogene
• 影响因子: 8
• 作者: Gillen SL;Waldron JA;Bushell M
• 通讯作者: Bushell M