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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.

项目总结我们研究的长期目标是确定基因表达是如何在后转录水平。控制信使RNA的翻译和降解是重要的基础生物过程包括发育、生育和神经功能。拟议的工作重点是典型的mRNA调节因子小果蝇(Pum)，属于RNA结合蛋白家族它们在整个尤卡里亚都是保守的。PUM结合了一组广泛的mRNA，包括那些编码关键发育形态因子。一旦与mRNA结合，Pum就会抑制编码的蛋白。我们发现Pum加速了靶mRNA的衰退，拟议的研究试图发现 Pum介导的mRNA降解机制。我们开发了新的方法来测量Pum的活性果蝇细胞，并发现了多个独特的抑制结构域，有效地抑制了目标mRNA。在……里面在前期工作中，我们确定了Pum抑制所必需的关键辅助抑制因子。在第一个目标中，我们测量抑制域对蛋白质表达和mRNA降解的影响并询问两类信使核糖核酸衰变因子在Pum抑制结构域抑制中的作用。我们询问共抑制物与每个Pum抑制结构域的物理相互作用并测量它们被招募到受PUM调控的靶向RNA。在第二个目标中，我们调查每个Pum的作用胚胎发育中的抑制域与基因表达的适当时空调控在早期发育过程中。这项研究将揭示Pum抑制的新机制。由此产生的这些发现有望广泛地增强我们对转录后调控的理解，特别是提高在发育、生育、干细胞增殖和神经系统方面的基因调控知识。

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。