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The let-7 Regulatory Network

let-7 监管网络

基本信息

批准号：
9027441
负责人：
Leemor Joshua-Tor
金额：
$ 34.56万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-10 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027441
关键词：
Address Animals Binding Biochemical Biogenesis Cells Chromatin Structure Colorectal Cancer Complex Development Down-Regulation Enzymes Exonuclease Family Funding Gene Expression Gene Silencing Genome Goals Human In Vitro Link Malignant Neoplasms Malignant neoplasm of liver Mediating Messenger RNA MicroRNAs Modification Molecular Nephroblastoma Oncogenes Pathway interactions Perlman syndrome Plants Play Post-Transcriptional Regulation Quality Control RNA Degradation RNA Interference Regulation Renal carcinoma Request for Proposals Role Signal Transduction Somatic Cell Specificity Stem cells Structure Tail Tumor Suppressor Proteins Uridine base biophysical techniques cancer cell embryonic stem cell glucose metabolism interest mRNA Transcript Degradation overexpression pluripotency public health relevance repaired tissue regeneration

项目摘要

DESCRIPTION (provided by applicant) RNA interference (RNAi) plays an important role in development, post-transcriptional regulation of gene expression in plants and animals and can impact genome organization and chromatin structure. While many studies focus on the identification of microRNA (miRNA) targets and the various downstream mechanisms of gene silencing, here we are interested in the regulation of a particular miRNA, let-7. The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Alternatively, Lin28 overexpression is correlated with the onset of numerous cancers, while let-7, a tumor suppressor, silences several human oncogenes. The Lin28/let-7 pathway is like a bistable switch. Each molecule represses expression of the other, and once the cell changes its state, the result is differentiation, or if the switch is reversed, cancer. At t h e molecular l e e l , Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3' oligouridylation activity of TUT4 and/or TUT7. The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by the exonuclease Dis3L2. In somatic cells, in the absence of L i n 2 8 , TUT4/7 promotes let-7 biogenesis by catalyzing single uridine addition to a subset of pre-let-7 miRNAs. Here, we propose to study the molecular basis of Lin28 mediated recruitment of TUT4/7 to pre-let-7, the switch in TUT4/7 activity between a monouridylase in the absence of Lin28 and an oligouridylase in the presence of Lin28, and the subsequent degradation of pre-let-7 by Dis3L2. We will utilize a similar approach to initiate an understanding of the broader role of TUT4/7 in marking both miRNA and mRNA with untemplated uridines.