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 基因表达调控是维持细胞内环境稳定的关键。基因失调会破坏 正常的细胞生理学，并经常导致疾病，如癌症，发育障碍， 神经退行性疾病然而，基因调控发生在不同的水平上，许多基因是 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mRNA，如果翻译，将是有害的 质量控制（Quality Control）这些过程涉及核糖核酸酶和突变的作用 在这些酶中有几种被发现会引起人类疾病。然而，酶的种类繁多， 参与这些过程尚未完全揭示，许多罕见的遗传性疾病 未知的潜在原因。此外，即使是具有已知核糖核酸酶功能的蛋白质， 表征了因此，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，最终目的是更好地了解这些必要的基因表达- 调节过程。该提案的第一个目标将是鉴定核酸内切酶靶标和特异性核酸内切酶。 切割位点，这将使用简化的生物信息学方法来完成。此外，这项研究 将鉴定核酸内切酶靶识别的序列特异性和/或结构决定簇， 切割，确定亚细胞定位对靶选择的影响，研究酶的 对细胞内稳态的贡献，并确定核酸内切酶的生理后果。 失调从分子水平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调控网络的理解中的相当大的空白。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， 和人类疾病的表现形式。