权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Repeat-containing RNA Binding Proteins of Trypanosomes

含有重复序列的锥虫 RNA 结合蛋白

基本信息

批准号：
8884913
负责人：
Inna Afasizheva
金额：
$ 40.93万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-05 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884913
关键词：
Action Potentials Address African Trypanosomiasis Amino Acids Animal Model Appearance Area Binding Biochemical Biochemistry Biogenesis Biological Assay Biology Code Complex Country Crystallography DNA Structure Deposition Disadvantaged Disease Drug Targeting Drug resistance Due Process Ensure Enzymes Event Family Gene Expression Gene Expression Profile Genetic Genome Goals Guide RNA Health Hazards Helix-Turn-Helix Motifs Human Investigation Left Mass Spectrum Analysis Mastigophora Mediating Messenger RNA Mitochondria Mitochondrial RNA Modification Molecular Biology Monitor Nature Nuclear Open Reading Frames Organism Parasites Parasitology Pathway interactions Phosphodiesterase I Polyadenylation Polynucleotide Adenylyltransferase Process Protein Engineering Proteins Proteomics Publishing RNA RNA Binding RNA Editing RNA Processing RNA Sequences RNA-Binding Proteins Reaction Recruitment Activity Repression Research Ribosomal RNA Ribosomes Role Shapes Small RNA Source Specificity Structure Tail Testing Therapeutic Therapeutic Intervention Transcript Translations Trypanosoma Trypanosoma brucei brucei Work base blocking factor crosslink deep sequencing health economics in vivo insertion/deletion mutation mRNA Decay mRNA Precursor mRNA Stability member public health relevance resistant strain transcriptome sequencing vector control

项目摘要

DESCRIPTION (provided by applicant): Diseases caused by Trypanosoma brucei spp. represent health hazards for many disadvantaged countries. Because of failing vector control and the rise of drug-resistance, the re-appearance of African sleeping sickness necessitates a search for new drug targets with emphasis on parasite-specific processes. Trypanosomal mitochondrial RNA processing pathways are extremely divergent from those of humans and represent a potential source of therapeutic intervention points. The mRNA editing has been extensively studied, but the significance of pre- and post-editing processing events emerged only recently. We discovered the mitochondrial poly (A) polymerase (KPAP1) and terminal uridyltransferase (RET1), and showed that intertwined polyadenylation and uridylation processes are critical for mRNA stability, translation and decay. In these studies, I encountered a diverse family of pentatricopeptide (PPR, 35 amino acids) helical repeat- containing RNA binding proteins that populate polyadenylation and translation complexes. By focusing on mRNA 3' end definition, modification and stability, this proposal introduces PPR proteins as key regulators of mitochondrial gene expression. The experimental approaches involve biochemistry, proteomics, crystallography, genetics and deep RNA sequencing. The proposal aims to: 1) Dissect general and transcript-specific mRNA adenylation/uridylation mechanisms. I hypothesize that the two modes of 3' modification, pre-editing addition of a short A-tail and post-editing A/U-tailing, serve discrete purposes of mRNA stabilization and commitment to translation, respectively. 2) Determine principles of uridylation- based mRNA decay. A hypothesis that RET1 TUTase-catalyzed uridylation accelerates mRNA 3'-5' degradation will be tested. I also posit that most transcripts are stabilized by a specific PPR protein that blocks mRNA uridylation. 3) Elucidate functions of a putative mRNA 3' definition and stabilization factor. I suggest that a PPR factor is deposited onto the pre-mRNA prior to polyadenylation to define the 3' end. We focus on select PPR proteins in trypanosomes, but the long term goal is to illuminate the mechanisms of RNA recognition by repeat-containing proteins, which will be of fundamental importance for RNA processing and mitochondrial biology fields.