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Novel Regulatory Mechanisms of Drosophila Pumilio

果蝇 Pumilio 的新型调控机制

基本信息

批准号：
10312121
负责人：
Aaron Charles Goldstrohm
金额：
$ 32.12万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312121
关键词：
Address Affect Ataxia Binding Biological Biological Assay Biological Process C-terminal Cancer Biology Cell Proliferation Cells Complex Data Defect Development Drosophila genus Embryo Embryonic Development Epilepsy Family Fertility Funding Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Health Human Human Biology Infertility Knowledge Malignant Neoplasms Mammals Maternal Messenger RNA Measures Mediating Memory Messenger RNA Modeling Molecular Motor N-terminal Nerve Degeneration Nervous System Physiology Nervous system structure Neurons Orthologous Gene Phenotype Poly(A)-Binding Proteins Post-Transcriptional Regulation Process Proteins RNA RNA Binding RNA Decay RNA Degradation RNA Recognition Motif RNA-Binding Proteins Regulation Repression Repressor Proteins Research Response Elements Role Specificity Structure System Testing Therapeutic Time Translational Repression Translations Work base egg genetic corepressor improved in vivo insight morphogens mutant nano nervous system disorder novel protein expression recruit stem cell proliferation stem cells

项目摘要

PROJECT SUMMARY The long term goal of our research is to determine how gene expression is regulated at the post- transcriptional level. Control of messenger RNA (mRNA) translation and degradation underlies important biological processes including development, fertility and neurological functions. The proposed work focuses on the archetypal mRNA regulator, Drosophila Pumilio (Pum), which belongs to a family of RNA-binding proteins that are conserved throughout eukarya. Pum binds an extensive group of mRNAs including those that encode key developmental morphogens. Upon binding to an mRNA, Pum represses expression of the encoded protein. We find that Pum accelerates decay of the target mRNA and the proposed research seeks to discover the mechanism of Pum-mediated mRNA degradation. We developed novel assays to measure Pum activity in Drosophila cells and discovered multiple unique Repression Domains that potently repress target mRNAs. In preliminary work, we identified key co-repressors that are necessary for Pum repression. In the first aim, we measure the impact of the Repression Domains on protein expression and mRNA degradation and interrogate the functional roles of two classes of mRNA decay factors in repression by each Pum Repression Domain. We interrogate the physical interactions of the co-repressors with each Pum Repression Domain and measure their recruitment to Pum-regulated target mRNAs. In the second aim, we investigate the role of each Pum Repression Domain in embryonic development and proper spatial and temporal control of gene expression during early development. This research will reveal novel mechanisms of Pum repression. The resulting discoveries are expected to broadly enhance our understanding of post-transcriptional control and specifically improve knowledge of gene regulation in development, fertility, stem cell proliferation, and the nervous system.

项目摘要我们研究的长期目标是确定基因表达是如何调节的，转录水平。信使RNA（mRNA）翻译和降解的控制是重要的包括发育、生育和神经功能在内的生物过程。拟议工作的重点是原型mRNA调节子，果蝇Pumilio（Pum），属于RNA结合蛋白家族在整个真核生物中都保存着。Pum结合了大量的mRNA，包括那些编码关键的发育形态因子。在与mRNA结合后，Pum抑制编码的蛋白我们发现Pum加速了靶mRNA的衰变，并且拟议的研究旨在发现 Pump介导的mRNA降解机制。我们开发了新的测定方法来测量Pum活性，果蝇细胞，发现了多个独特的抑制结构域，有效地抑制靶mRNA。在在初步工作中，我们确定了Pum抑制所必需的关键辅抑制因子。第一个目标，我们测量阻遏结构域对蛋白质表达和mRNA降解的影响，两类mRNA衰减因子在每个Pum阻遏结构域阻遏中的功能作用。我们询问辅阻遏物与每个Pum阻遏结构域的物理相互作用，并测量将其募集到Pump调节的靶mRNA。在第二个目标中，我们研究了每个Pum的作用，胚胎发育中的阻遏结构域与基因表达的时空调控在早期发展中。这项研究将揭示Pum抑制的新机制。所得这些发现有望广泛增强我们对转录后控制的理解，提高对发育、生育、干细胞增殖和神经系统基因调控的认识。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A conserved domain of Drosophila RNA-binding protein Pumilio interacts with multiple CCR4-NOT deadenylase complex subunits to repress target mRNAs.

DOI：
10.1016/j.jbc.2022.102270
发表时间：
2022-09
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Haugen, Rebecca J.;Arvola, Rene M.;Connacher, Robert P.;Roden, Richard T.;Goldstrohm, Aaron C.
通讯作者：
Goldstrohm, Aaron C.

Preparation of cooperative RNA recognition complexes for crystallographic structural studies.

用于晶体结构研究的协作 RNA 识别复合物的制备。

DOI：
10.1016/bs.mie.2019.04.001
发表时间：
2019
期刊：
Methods in enzymology
影响因子：
0
作者：
Qiu,Chen;Goldstrohm,AaronC;TanakaHall,TraciM
通讯作者：
TanakaHall,TraciM

The RNA binding domain of Pumilio antagonizes poly-adenosine binding protein and accelerates deadenylation.

DOI：
10.1261/rna.046029.114
发表时间：
2014-08
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Weidmann CA;Raynard NA;Blewett NH;Van Etten J;Goldstrohm AC
通讯作者：
Goldstrohm AC

Human Pumilio proteins directly bind the CCR4-NOT deadenylase complex to regulate the transcriptome.

DOI：
10.1261/rna.078436.120
发表时间：
2021-04
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Enwerem III;Elrod ND;Chang CT;Lin A;Ji P;Bohn JA;Levdansky Y;Wagner EJ;Valkov E;Goldstrohm AC
通讯作者：
Goldstrohm AC

Combinatorial control of messenger RNAs by Pumilio, Nanos and Brain Tumor Proteins.

Pumilio，Nanos和脑肿瘤蛋白对Messenger RNA的组合控制。