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The identification of fundamental molecular regulators of ribosomal DNA and nucleolar organization in fission yeast

裂殖酵母核糖体 DNA 和核仁组织基本分子调节因子的鉴定

基本信息

批准号：
10154642
负责人：
Alexandria Jane Cockrell
金额：
$ 3.45万
依托单位：
STOWERS INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-03 至 2024-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154642
关键词：
Address Architecture Area Automobile Driving Bacterial DNA Biogenesis Biological Models Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Nucleolus Cell physiology Cells Cellular biology Chromosome Structures Chromosomes DNA DNA analysis DNA-Binding Proteins Exhibits Fission Yeast Fluorescence Microscopy Future Genetic Genetic Transcription Genome Goals Human Image Image Analysis Imaging Device Interphase Knowledge Label Maintenance Malignant Neoplasms Measures Methods Modeling Molecular Molecular Biology Molecular Biology Techniques Molecular and Cellular Biology Morphology Neurodegenerative Disorders Nuclear Nucleolar Organizer Region Nucleolar Proteins Organelles Organism Physiologic pulse Process Production Protein Biosynthesis Proteins Quantitative Microscopy RNA RNA Processing Research Ribosomal DNA Ribosomal Proteins Ribosomal RNA Ribosomes Role Saccharomycetales Structure Testing Transcript Variant cell growth deletion library field study genetic approach genetic manipulation genome-wide high throughput analysis human disease imaging genetics innovation mutant novel novel strategies nucleolar organizing region protein complex tool

项目摘要

Project Abstract Ribosome production relies on a nuclear organelle called the nucleolus. Within this structure, ribosomal DNA (rDNA) is transcribed to form RNA transcripts that associate with ribosomal proteins. Nucleolar architecture is altered in many human diseases including numerous cancers, prompting several studies to search for regulators of nucleolar morphology. While these studies rely on analysis of nucleolar proteins or ribosome production to identify molecular regulators, few studies have defined cell cycle-specific mechanisms for regulating nucleolar structure. Furthermore, no studies have examined the impact of rDNA spatial organization on nucleolar morphology despite rDNA loci’s known role as Nucleolar Organizer Regions. The long-term goal is to understand conserved regulatory mechanisms of rDNA and nucleolar organization. The overall objectives of this proposal are to (i) to identify molecular regulators of rDNA spatial organization and (ii) define the processes driving cell cycle-regulated nucleolar morphology. The central hypothesis is that the spatial organization of rDNA is regulated, in part, by chromosome organizing proteins and ribosome biogenesis; furthermore, these ribosome biogenesis processes are cell cycle-regulated, driving dynamic reorganization of nucleolar morphology during interphase. The rationale for this study is that identification of conserved molecular regulators of rDNA and nucleolar organization in fission yeast will provide a template for future research in higher organisms. This central hypothesis will be tested by two specific aims: 1) identify molecular regulators of rDNA spatial organization in fission yeast; and 2) define the processes driving cell cycle-regulated nucleolar morphology. For aim 1, a novel tool for analysis of rDNA spatial organization in live cells has been developed in fission yeast. This tool will be used to quantify rDNA spatial organization by fluorescence microscopy in candidate mutants with altered chromosome organization and DNA topology factors. This analysis will be expanded by a genome-wide high-throughput imaging screen to broadly identify regulators of rDNA spatial organization. Aim 2 will apply fluorescence microscopy, cell biology, and molecular biology approaches to examine the role of cell cycle-regulated ribosome biogenesis factors in interphase nucleolar morphology. These studies examine rDNA and nucleolar morphology in fission yeast, a model system notable for its application to higher organisms and ease of genetic manipulation. To understand the relationship between nucleolar morphology and human disease, the regulatory mechanisms behind rDNA and nucleolar organization must be identified. This study applies innovative imaging tools with advanced cellular and molecular biology techniques to broadly identify fundamental molecular regulators of rDNA and nucleolar morphology, providing a framework for future studies in human cells.

项目摘要