Regulated transcript stability
调节转录稳定性
基本信息
- 批准号:BB/E017657/1
- 负责人:
- 金额:$ 45.5万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2007
- 资助国家:英国
- 起止时间:2007 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Now that the genetic blueprint of many organisms has been deciphered, the next big challenge in Biology is to understand how the instructions are used to make a living creature. This highlights the subject of gene regulation, the study of which genes are in use at any time. One of the least understood parts is how the cell quickly gets rid of working copies of genes (the messenger RNA, mRNA, transcripts) once they are no longer needed. Several pathways are known that degrade mRNA, but the controls to protect mRNA that is still required while swiftly removing unwanted mRNA are little understood. It is likely that this fundamental level of gene control will have similar features in all organisms, with signalling and control systems exquisitely adapted for group of genes or even individual important genes according to the processes in which they are involved. Controlled mRNA degradation is a major regulatory mechanism in nitrogen metabolism in the filamentous fungus Aspergillus nidulans. We have recently identified the molecule (glutamine) that signals accelerated decay of some, but not all, mRNAs involved in nitrogen metabolism when there is sufficient good-quality nitrogen source available to the fungus. An even more exciting aspect is the discovery that a second molecule (nitrate) opposes this signal for specific mRNAs. It therefore provides an excellent way to identify and characterise the components that regulate mRNA stability. This well-studied system has all the genetic, information and technical resources to tackle the problem of how one mRNA remains stable while another is destroyed within minutes as the fungus responds to different nitrogen sources. The essential first step in mRNA degradation is to remove the poly(A) tail from the molecule. Enzyme complexes, highly conserved among all forms of life, contain proteins that carry out this function although the details remain to be uncovered. Based on our initial experiments, we propose that one protein, Ccr4p, is the main deadenylase for general mRNA decay, while another, Pop2p, is needed in specific regulated pathways. We will confirm and further characterise these proteins within this project, including how their activity against specific mRNAs is inhibited by the specific signal nitrate. Additional proteins must be required to regulate degradation and we have identified three promising candidates from initial experiments and bioinformatics analysis. We will characterise their functions and also carry out experiments to identify further regulatory proteins. Monitoring the half-lives of individual mRNAs is one of our basic techniques. DNA microarrays will let us see the global effects of these regulatory proteins. However, we will also use methodologies from classical genetic analysis, site-specific mutagenesis, protein tagging, two and three hybrid analysis and co-immunoprecipitation to achieve our goals. One further approach that we will use is real-time imaging to gain new insights into the spatial aspects of mRNA turnover, in collaboration with laboratories that are very experienced with cell imaging and the use of fluorescently tagged proteins in A. nidulans. Research into the co-ordination of mRNA degradation as part of gene regulation and signalling is in its infancy and this elegant system within an amenable organism will allow us to make a significant contribution.
既然许多生物体的遗传蓝图已经被破译,生物学的下一个重大挑战是了解这些指令是如何用来制造生物的。这突出了基因调控的主题,即研究哪些基因在任何时候都在使用。人们最不了解的部分之一是,一旦不再需要基因(信使RNA、mRNA、转录本)的工作拷贝,细胞如何迅速摆脱它们。已知有几种降解mRNA的途径,但在快速去除不需要的mRNA的同时仍然需要保护mRNA的控制却知之甚少。基因控制的这一基本水平很可能在所有生物体中都具有相似的特征,信号和控制系统根据它们所参与的过程,对一组基因甚至个别重要基因进行了精心的调整。mRNA受控降解是丝状真菌构巢曲霉氮代谢的主要调控机制。我们最近发现了一种分子(谷氨酰胺),当真菌有足够的优质氮源时,它会加速参与氮代谢的一些(但不是全部)mRNA的衰变。一个更令人兴奋的方面是发现第二种分子(硝酸盐)对抗特定mRNA的这种信号。因此,它提供了一个很好的方法来识别和鉴定调节mRNA稳定性的成分。这个经过充分研究的系统拥有所有的遗传、信息和技术资源,可以解决一种mRNA如何保持稳定,而另一种mRNA如何在真菌对不同氮源做出反应时在几分钟内被破坏的问题。mRNA降解的基本第一步是从分子中去除poly(A)尾。酶复合物在所有生命形式中高度保守,含有执行此功能的蛋白质,尽管细节仍有待发现。基于我们最初的实验,我们提出,一种蛋白质,Ccr4p,是一般mRNA衰变的主要deadenylase,而另一种,Pop2p,需要在特定的调节途径。我们将在本项目中确认并进一步研究这些蛋白质,包括它们对特定mRNA的活性如何被特定的信号硝酸盐抑制。必须需要额外的蛋白质来调节降解,我们已经从初步实验和生物信息学分析中确定了三种有希望的候选蛋白质。我们将研究它们的功能,并进行实验以确定进一步的调节蛋白。监测单个mRNA的半衰期是我们的基本技术之一。DNA微阵列将让我们看到这些调节蛋白的全球影响。然而,我们也将使用经典的遗传分析,定点诱变,蛋白质标签,两个和三个杂交分析和免疫共沉淀的方法来实现我们的目标。我们将使用的另一种方法是实时成像,以获得对mRNA周转空间方面的新见解,与在细胞成像和使用荧光标记蛋白质方面非常有经验的实验室合作。nidulans。作为基因调控和信号传导的一部分,对mRNA降解协调的研究还处于起步阶段,在一个顺从的生物体中,这个优雅的系统将使我们能够做出重大贡献。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
RrmA regulates the stability of specific transcripts in response to both nitrogen source and oxidative stress.
- DOI:10.1111/mmi.12324
- 发表时间:2013-09
- 期刊:
- 影响因子:3.6
- 作者:Krol K;Morozov IY;Jones MG;Wyszomirski T;Weglenski P;Dzikowska A;Caddick MX
- 通讯作者:Caddick MX
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mark Caddick其他文献
Characterisation of AnBEST1, a functional anion channel in the plasma membrane of the filamentous fungus, <em>Aspergillus nidulans</em>
- DOI:
10.1016/j.fgb.2011.05.004 - 发表时间:
2011-09-01 - 期刊:
- 影响因子:
- 作者:
Stephen K. Roberts;James Milnes;Mark Caddick - 通讯作者:
Mark Caddick
Mark Caddick的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Mark Caddick', 18)}}的其他基金
MRI: Acquisition of an Electron Microprobe
MRI:电子显微探针的采集
- 批准号:
2018840 - 财政年份:2020
- 资助金额:
$ 45.5万 - 项目类别:
Standard Grant
Durations and Rates of High Temperature Metamorphism During Archean Orogenesis: Implications for Early Earth's Tectonics
太古代造山作用期间高温变质作用的持续时间和速率:对早期地球构造的影响
- 批准号:
1447568 - 财政年份:2015
- 资助金额:
$ 45.5万 - 项目类别:
Continuing Grant
Collaborative Research: Field-Based Quantification of Dehyration Flux from Subducting Lithologies, Syros and Sifnos, Greece
合作研究:希腊锡罗斯岛和锡夫诺斯岛俯冲岩性脱水通量的现场定量
- 批准号:
1250470 - 财政年份:2013
- 资助金额:
$ 45.5万 - 项目类别:
Continuing Grant
Exploring the transcriptome of Aspergillus nidulans
探索构巢曲霉的转录组
- 批准号:
BB/H020365/1 - 财政年份:2010
- 资助金额:
$ 45.5万 - 项目类别:
Research Grant
相似国自然基金
Cart基因保护缺血性脑损害及其分子机制的研究
- 批准号:30470612
- 批准年份:2004
- 资助金额:22.0 万元
- 项目类别:面上项目
相似海外基金
The Role of Inosine Monophosphate Dehydrogenase in mRNA Regulation: Identification of mRNAs Bound and Functional Consequences
肌苷单磷酸脱氢酶在 mRNA 调节中的作用:鉴定 mRNA 结合和功能后果
- 批准号:
10796269 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
Role of RNA helicase Ddx5 in pathological cardiac remodeling
RNA解旋酶Ddx5在病理性心脏重塑中的作用
- 批准号:
10718560 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
Defining the mechanisms by which mutations in DNAJC7 increase susceptibility to ALS/FTD
确定 DNAJC7 突变增加 ALS/FTD 易感性的机制
- 批准号:
10679697 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
Viral disruption of host transcriptome integrity
病毒破坏宿主转录组完整性
- 批准号:
10666992 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
TET2-mediated epitranscriptomic regulation in leukemia microenvironment
TET2介导的白血病微环境中的表观转录组调控
- 批准号:
10801348 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
Biogenesis of mRNA-derived telomerase long noncoding RNA
mRNA 衍生端粒酶长非编码 RNA 的生物发生
- 批准号:
10638429 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
Molecular Basis for mRNA Decay in Bacteria - summer supplement
细菌 mRNA 衰变的分子基础 - 夏季补充品
- 批准号:
10805871 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
In utero rescue of cleft lip and palate in a humanized mouse model
人源化小鼠模型中唇裂和腭裂的子宫内抢救
- 批准号:
10645829 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别:
The biogenesis and functions of pre-meiotic small RNAs in male reproductive development in maize
减数分裂前小RNA在玉米雄性生殖发育中的生物发生和功能
- 批准号:
10718996 - 财政年份:2023
- 资助金额:
$ 45.5万 - 项目类别: