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

• 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
• 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' Untranslated Regions; 5' 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

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.

说明书(申请人提供)：snoRNAs是一种非编码引导RNA，可指导其靶RNA的位点特异性转录后RNA修饰--假脱氧核糖核酸化或2‘-O-甲基化。虽然snoRNAs的生化功能相对较好，但它们的生物学作用才刚刚开始探索。值得注意的是，特定snoRNAs的失调与乳腺癌、前列腺癌、肺癌、脑癌和结直肠癌以及白血病和多发性骨髓瘤的风险增加有关。最值得注意的是，最近发现了一种假尿嘧啶核糖核酸，SNORA42，它是非小细胞肺癌(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活性改变导致癌症的机制仍然是个谜。我们有初步数据支持snoRNA功能的新范式，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。利用一种新的技术(伪序列)，我们可以单核苷酸分辨率在全基因组范围内定位伪尿苷(φ)的位置，我们首次证明了内源性人类信使RNA(MRNAs)在特定的位置含有φ‘S。由于以前已知的snoRNA靶标仅限于核糖体RNA，或较少发生剪接小RNA，这一突破使SNORA42的潜在癌症相关靶标的数量增加了100多倍，并增加了癌基因SNORA42的扩增/过度表达通过干扰mRNA靶标的修改而导致肿瘤发生的可能性。尽管内源性信使核糖核酸假尿酸的分子后果仍有待确定，但最近的工作戏剧性地说明了这种转录后信使核糖核酸修饰的潜在意义：将φ‘S人工掺入模型信使核糖核酸改变了遗传密码的含义！在这些发现的基础上，我们建议进行一项探索性研究计划：(1)研究非小细胞肺癌中位点特异性mRNA假脱氧核糖核酸的分子和细胞效应；(2)全面鉴定snoRNA癌基因SNORA42的假脱氧核糖核酸化靶点。总之，拟议的研究将阐明SNORA42过度表达/基因组扩增导致预后不良的肺癌的机制。