The role of RNA in the response to cellular stress

RNA 在细胞应激反应中的作用

• 批准号: MC_UU_00025/6
• 负责人: Martin Bushell
• 金额: $ 9.68万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Intramural
• 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=MC_UU_00025%2F6
• 关键词: role; RNA; response; cellular; stress

Recently, a new gene delivery system has been developed, to specifically provide diseased cells with a particular protein to correct cell function. This method using messenger RNA molecules as a delivery vehicle. By changing the RNA molecules different proteins can be encoded on these RNA molecules and different human disease can be treated. However, our lack of understanding of these molecules has resulted in safety issue, which need to be resolved before they can be used to treat a large range of human diseases. Our laboratory has been investigating how RNAs are regulated and we have discovered that two particular RNA binding proteins associate with translationally repressed mRNAs. Using methods developed in our laboratory we can now identify RNA repression mechanisms operating in different tissues and thus tailor these RNA molecules for specific delivery to different tissue types, reducing toxic side effects. We will determine the applicability of this approach to identify the repertoire of repressive mechanisms operating within a cell, in order to engineer therapeutic-mRNAs for restricted on-target expression in particular tissues/cell types and disease states. This will facilitate the development of the next generation of mRNA-based therapeutics which will be specifically designed to minimise potential off-target adverse effects.

最近，已经开发出一种新的基因递送系统，专门为患病细胞提供特定的蛋白质以纠正细胞功能。这种方法使用信使RNA分子作为传递载体。通过改变RNA分子，可以在这些RNA分子上编码不同的蛋白质，并且可以治疗不同的人类疾病。然而，我们对这些分子缺乏了解导致了安全性问题，在它们用于治疗大范围的人类疾病之前需要解决这些问题。我们的实验室一直在研究RNA是如何被调节的，我们发现两种特定的RNA结合蛋白与被抑制的mRNA相关。使用我们实验室开发的方法，我们现在可以识别在不同组织中起作用的RNA抑制机制，从而定制这些RNA分子，以特异性地递送到不同的组织类型，减少毒副作用。我们将确定这种方法的适用性，以确定在细胞内操作的抑制机制的库，以工程治疗mRNA的限制在特定的组织/细胞类型和疾病状态中的靶向表达。这将促进下一代基于mRNA的治疗药物的开发，这些药物将专门设计用于最大限度地减少潜在的脱靶不良反应。

项目成果

Damage-Net: A program for DNA repair meta-analysis identifies a network of novel repair genes that facilitate cancer evolution.

• DOI: 10.1016/j.dnarep.2021.103158
• 发表时间: 2021-09
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Bader AS;Bushell M
• 通讯作者: Bushell M

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

Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair.

• DOI: 10.1038/s41467-018-02893-x
• 发表时间: 2018-02-07
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lu WT;Hawley BR;Skalka GL;Baldock RA;Smith EM;Bader AS;Malewicz M;Watts FZ;Wilczynska A;Bushell M
• 通讯作者: Bushell M

MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus.

• DOI: 10.1038/s41419-018-0628-4
• 发表时间: 2018-05-29
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Godfrey JD;Morton JP;Wilczynska A;Sansom OJ;Bushell MD
• 通讯作者: Bushell MD

TAp73 contributes to the oxidative stress response by regulating protein synthesis.

• DOI: 10.1073/pnas.1718531115
• 发表时间: 2018-06-12
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Marini A;Rotblat B;Sbarrato T;Niklison-Chirou MV;Knight JRP;Dudek K;Jones C;Bushell M;Knight RA;Amelio I;Willis AE;Melino G
• 通讯作者: Melino G