Characterizing functional targets of a non-coding RNA oncogene, SNORA42

表征非编码 RNA 癌基因 SNORA42 的功能靶点

基本信息

批准号：
8878689
负责人：
Wendy Victoria Gilbert
金额：
$ 19.14万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878689
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Affect Amino Acid Sequence Amino Acids Awareness Biochemical Biological Biological Assay Biology Breast Cancer Etiology Cancer Patient Cell Line Cell Proliferation Cell physiology Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Code Colorectal Cancer Data Disease Epithelial Cells Functional disorder Gene Expression Regulation Gene Targeting Genes Genetic Code Genomics Guide RNA Health Human Investigation Knowledge Lead Link Location Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Malignant neoplasm of prostate Maps Mass Spectrum Analysis Mediating Medical Messenger RNA Metastatic to Methylation Modeling Modification Molecular Molecular Target Multiple Myeloma Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal Cell Nucleotides Oncogenes Oncogenic Point Mutation Post-Transcriptional RNA Processing Property Proteins Pseudouridine RNA RNA Stability Reporter Research Resolution Ribosomal RNA Risk Role Sense Codon Site Small Nucleolar RNA Small RNA Terminator Codon Therapeutic Time Translations United States Untranslated RNA Woman Work cell growth cell motility design established cell line genome editing genome-wide insight leukemia lung Carcinoma men new technology outcome forecast overexpression prevent programs research study tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): snoRNAs are non-coding guide RNAs that direct site-specific post-transcriptional RNA modifications - either pseudouridylation or 2'-O-methylation - of their target RNAs. Although snoRNAs' biochemical functions are relatively well characterized, their biological roles are just beginning to be explored. Notably, dysregulation of specific snoRNAs is associated with increased risk for breast, prostate, lung, brain and colorectal cancers as well as leukemia and multiple myeloma. Most remarkably, one pseudouridylation-directing snoRNA, SNORA42, was recently identified as an oncogene in non-small cell lung carcinoma (NSCLC). Despite increasing awareness of the medical significance of snoRNA biology, the mechanisms by which altered snoRNA activities cause cancer remain mysterious. We have preliminary data supporting a new paradigm for snoRNA function, which we here propose to investigate in the context of increased NSCLC cell proliferation and metastasis. Using a novel technology (Pseudo-seq) that allows us to map the locations of pseudouridines (φ) genome-wide with single nucleotide resolution, we have demonstrated for the first time that endogenous human messenger RNAs (mRNAs) contain φ's at specific sites. Because previously known snoRNA targets were restricted to ribosomal RNAs, or less frequently, spliceosomal small RNAs, this breakthrough expands the number of potential cancer-relevant targets of SNORA42 more than 100-fold, and raises the possibility that amplification/over-expression of oncogenic SNORA42 causes tumorigenesis by perturbing modification of mRNA targets. Although the molecular consequences of endogenous mRNA pseudouridylation remain to be determined, recent work dramatically illustrates the potential significance of this post-transcriptional mRNA modification: artificial incorporation of φ's into model mRNAs changes the meaning of the genetic code! Building on these discoveries, we propose to conduct an exploratory research program (1) to investigate the molecular and cellular effects of site-specific mRNA pseudouridylation in non-small cell lung carcinoma; and (2) to comprehensively identify the pseudouridylated targets of the snoRNA oncogene SNORA42. Together, the proposed investigations will illuminate the mechanisms by which over-expression/genomic amplification of SNORA42 contributes to lung cancer with poor prognosis.

描述（由适用提供）：SNORNAS是非编码指南RNA，其目标RNA的转录后特异性转录RNA修饰 - 假胞苷化或2'-O-甲基化。尽管snornas的生化功能的特征相对较好，但它们的生物学作用才刚刚开始探索。值得注意的是，特定snORNA的失调与乳房，前列腺，肺，脑和有色癌症以及白血病和多发性骨髓瘤的风险增加有关。最引人注目的是，最近在非小细胞肺癌（NSCLC）中确定了一个假胞素化导向snorna，snora42。尽管对SNORNA生物学的医学意义的认识越来越高，但改变的SNORNA活动导致癌症的机制仍然神秘。我们拥有使用一种新技术（伪seq）来支持新的SNORNA功能范式的初步数据，该技术使我们能够以单个核丁基分辨率来绘制拟南芥基因组（φ）基因组的位置，我们首次证明了内源性人类Messenger RNAS（MRNAS）首次包含特定部位的内源性人类Messenger RNA（MRNAS）。由于以前已知的SNORNA靶标仅限于核糖体RNA，或者较少频率地夹层小RNA，因此这一突破会扩大了100倍以上的SNORA42潜在癌症与癌症靶标的数量，并提高了Oncenic Snora42的扩增/过表达通过pertraiging pertraigation tarmorigansis的放大/过表达。尽管内源性mRNA假基因化的分子后果仍有待确定，但最近的工作大大说明了这种转录后mRNA修饰的潜在意义：将φ的人工掺入到模型mRNA中，改变了遗传密码的含义！在这些发现的基础上，我们建议开展探索性研究计划（1），以研究位点特异性mRNA假胞苷化在非小细胞肺癌中的分子和细胞效应；（2）全面识别SNORNA ONCOGENE SNORA42的伪基化靶标。拟议的投资将共同阐明SNORA42过表达/基因组扩增的机制，导致预后不良的肺癌。