The Roles of Rnt1 and Putative Endoribonucleases in mRNA Processing and Degradation

Rnt1 和假定的核糖核酸内切酶在 mRNA 加工和降解中的作用

• 批准号: 10607217
• 负责人: Lee-Ann Shari Notice
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-29 至 2025-12-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607217
• 关键词: 3-Dimensional; Acute; Affect; Attention; Bioinformatics; Cartilage-hair hypoplasia; Catalytic Domain; Cell Cycle; Cell Nucleolus; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Characteristics; Complex; Cytoplasm; Data; Development; Disease; Endoribonucleases; Ensure; Enzymes; Essential Genes; Exonuclease; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Hereditary Disease; Homeostasis; In Vitro; Link; Malignant Neoplasms; Mediating; Mendelian disorder; Messenger RNA; Methods; Molecular; Mutation; Neurodegenerative Disorders; Normal Cell; Ontology; Pathway interactions; Physiological; Pontocerebellar hypoplasia; Post-Transcriptional Regulation; Process; Protein Biosynthesis; Proteins; Quality Control; RNA; RNA Decay; RNA Degradation; RNA Processing; RNA analysis; Research; Ribonucleases; Role; Site; Specificity; Stress; Structure; Techniques; Testing; Transcript; Transfer RNA; Translating; Untranslated RNA; Yeasts; biological adaptation to stress; carbohydrate metabolism; ciliopathy; developmental disease; endonuclease; human disease; in vivo; insight; mutant; posttranscriptional; prevent; protein function; stem; structural determinants; targeted nucleases

PROJECT SUMMARY Gene expression regulation is critical for maintaining cellular homeostasis. Dysregulation of genes disrupts normal cell physiology and very frequently leads to diseases such as cancer, developmental disorders, and neurodegenerative diseases. Gene regulation, however, occurs at different levels, and many genes are regulated post-transcriptionally at the RNA level. Two major methods of post-transcriptional gene regulation are RNA processing and RNA degradation, which function to regulate the steady-state level of different RNAs in the cell (quantity control) and to ensure the destruction of aberrant mRNAs that, if translated, would be deleterious to the cell (quality control). These processes involve the actions of enzymes called ribonucleases, and mutations in several of these enzymes have been found to cause human disease. Yet, the vast spectrum of enzymes involved in these processes has not been completely uncovered, and many rare inherited diseases have unknown underlying causes. Additionally, even proteins with known ribonuclease functions remain poorly characterized. Therefore, this project aims to investigate the roles of five proteins in messenger RNA (mRNA) processing and degradation, with the ultimate objective of better understanding these essential gene expression- regulating processes. The first goal of this proposal will be the identification of endonuclease targets and specific cleavage sites, which will be accomplished using a streamlined bioinformatics approach. Additionally, this study will identify the sequence-specific and/or structural determinants of endonuclease target recognition and cleavage, determine the impact of sub-cellular localization on target selection, investigate the enzymes' contributions to cellular homeostasis, and determine the physiological consequences of endonuclease dysregulation. Gaining molecular insight into the endonuclease functions of the proteins described in this study will fill considerable gaps in our current understanding of RNA regulatory networks. These discoveries could additionally reveal important links between the critical RNA control mechanisms of processing and degradation, and the manifestation of human disease.

项目概要 基因表达调控对于维持细胞稳态至关重要。基因失调会扰乱 正常的细胞生理机能，并且经常导致癌症、发育障碍等疾病 神经退行性疾病。然而，基因调控发生在不同的水平上，并且许多基因 在RNA水平上进行转录后调节。转录后基因调控的两种主要方法是 RNA加工和RNA降解，其功能是调节细胞中不同RNA的稳态水平 细胞（数量控制）并确保破坏异常的 mRNA，这些异常的 mRNA 如果被翻译，将是有害的 到细胞（质量控制）。这些过程涉及称为核糖核酸酶的酶的作用和突变 其中几种酶已被发现会引起人类疾病。然而，广泛的酶谱 这些过程所涉及的过程尚未完全被揭示，许多罕见的遗传性疾病已经被揭示出来。 未知的根本原因。此外，即使具有已知核糖核酸酶功能的蛋白质仍然很差 特点。因此，本项目旨在研究信使RNA（mRNA）中五种蛋白质的作用 加工和降解，最终目标是更好地理解这些重要的基因表达—— 调节流程。该提案的首要目标是确定核酸内切酶靶标和具体 切割位点，这将使用简化的生物信息学方法来完成。此外，本研究 将鉴定核酸内切酶靶标识别的序列特异性和/或结构决定因素，以及 切割，确定亚细胞定位对靶标选择的影响，研究酶的 对细胞稳态的贡献，并确定核酸内切酶的生理后果 失调。从分子角度深入了解本研究中描述的蛋白质的核酸内切酶功能 将填补我们目前对 RNA 调控网络理解的巨大空白。这些发现可以 另外揭示了加工和降解的关键 RNA 控制机制之间的重要联系， 以及人类疾病的表现。