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（由申请人提供）：snoRNA 是非编码指导 RNA，指导其靶标 RNA 的位点特异性转录后 RNA 修饰（假尿苷化或 2'-O-甲基化）。值得注意的是，特定 snoRNA 的失调也与乳腺癌、前列腺癌、肺癌、脑癌和结直肠癌的风险增加有关。最不寻常的是，一种指导假尿苷化的 snoRNA，SNORA42，最近被鉴定为非小细胞肺癌 (NSCLC) 的癌基因，尽管人们越来越认识到 snoRNA 生物学的医学意义，但 snoRNA 的作用机制。我们有初步数据支持 snoRNA 功能的新范例，我们在此建议在 NSCLC 细胞增殖和转移增加的背景下进行研究。一项新技术（伪序列）使我们能够以单核苷酸分辨率绘制全基因组范围内的伪尿苷 (φ) 位置，我们之前首次证明内源性人类信使 RNA (mRNA) 在特定位点含有 φ。已知的 snoRNA 靶点是核糖体 RNA，或者不太常见的是剪接体小 RNA，这一突破将 SNORA42 潜在癌症相关靶点的数量限制扩大了超过100 倍，并提出了致癌 SNORA42 的扩增/过度表达通过干扰 mRNA 靶标的修饰而导致肿瘤发生的可能性。转录 mRNA 修饰：将 φ 人工掺入模型 mRNA 改变了遗传密码的含义！基于这些发现，我们建议开展一项探索性研究计划 (1) 来研究(2) 全面鉴定 snoRNA 癌基因 SNORA42 的假尿苷化靶点，同时，拟议的研究将阐明过度表达/基因组的机制。 SNORA42 扩增导致肺癌预后不良。