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.

项目摘要 基因表达调节对于维持细胞稳态至关重要。基因的失调破坏 正常的细胞生理学，并且经常导致癌症，发育障碍和 神经退行性疾病。但是，基因调节发生在不同的水平，许多基因是 在RNA水平上进行转录后的调节。转录后基因调节的两种主要方法是 RNA处理和RNA降解，起作用，可调节不同RNA的稳态水平 细胞（数量控制），并确保破坏异常的mRNA，如果翻译为有害 到电池（质量控制）。这些过程涉及称为核糖珠和突变的酶的作用 在这些酶中的几种中，发现引起人类疾病。然而，大量的酶 参与这些过程尚未完全发现，许多罕见的遗传疾病有 未知的基本原因。另外，即使具有已知核糖核酸酶功能的蛋白质也保持较差 特征。因此，该项目旨在研究五种蛋白质在Messenger RNA（mRNA）中的作用 加工和降解，以更好地理解这些基因表达的最终目标 - 调节过程。该提案的第一个目标是确定核酸内切酶目标和特定目标 切割站点将使用简化的生物信息学方法来完成。此外，这项研究 将确定核酸内切酶靶标的序列特异性和/或结构决定因素，并 切割，确定亚细胞定位对靶标的影响，研究酶的影响 对细胞稳态的贡献，并确定核酸内切酶的生理后果 失调。获得对本研究描述的蛋白质核酸内切酶功能的分子见解 我们当前对RNA调节网络的理解将填补大量空白。这些发现可以 另外，揭示了处理和降解的关键RNA控制机制之间的重要联系， 以及人类疾病的表现。