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

项目总结 基因表达调控是维持细胞动态平衡的关键。基因调控失调会扰乱 正常的细胞生理，经常导致疾病，如癌症、发育障碍和 神经退行性疾病。然而，基因调控在不同的水平上发生，许多基因是 在RNA水平上进行转录后调控。转录后基因调控的两种主要方法是 RNA加工和RNA降解，它们的功能是调节不同RNAs在 细胞(数量控制)，并确保破坏异常的mRNAs，如果翻译，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，以及突变。 在其中的几种酶中，已经发现会导致人类疾病。然而，酶的广谱 参与这些过程还没有完全被发现，许多罕见的遗传性疾病 未知的潜在原因。此外，即使具有已知的核糖核酸酶功能的蛋白质也仍然很差。 特色化的。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。这项提议的第一个目标将是确定核酸内切酶靶标和特定的 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 将确定核酸内切酶靶标识别的序列特异性和/或结构决定因素 切割，确定亚细胞定位对靶标选择的影响，研究酶的 对细胞内稳态的贡献，并决定核酸内切酶的生理后果 监管失调。对本研究中描述的蛋白质的核酸内切酶功能有了分子上的了解 将填补我们目前对RNA调控网络了解的相当大的空白。这些发现可能 此外还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。

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.