Maturation of let-7 miRNAs

let-7 miRNA 的成熟

• 批准号: RGPIN-2020-05258
• 负责人: Legault, Pascale
• 金额: $ 3.64万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716040
• 关键词: Maturation; let; miRNAs

MicroRNAs (miRNAs) play important roles in the regulation of gene expression by recognizing messenger RNAs (mRNA) through sequence complementarity as part of the RNA-induced silencing complex (RISC). Typically, targeting an mRNA by formation of the miRNA-guided RISC leads to translational arrest and degradation of the mRNA. In humans, the genome encodes around 2,000 miRNAs, which have the potential to regulate over 60% of all mRNAs. Misregulation of miRNA levels can change gene expression patterns, and these changes have been directly linked to developmental defects and several human diseases. The miRNAs of the let-7 family are highly conserved across animal species and play several important roles in many biological processes. Given the key role of let-7 miRNAs as development regulators and tumor suppressors, their biogenesis is tightly regulated. This starts with transcription by RNA polymerase II of a primary miRNA (pri-miRNA), which undergoes two cleavage steps, first by the Drosha/DGCR8 (Microprocessor) complex to yield the precursor miRNA (pre-miRNA) and then by Dicer to yield a miRNA duplex. A number of recent studies have led to the general view that numerous post-transcriptional mechanisms regulate miRNA maturation and that this allows for specific temporal and spatial expression of miRNAs. Moreover, several proteins have been identified that target immature forms of let-7 miRNAs (pri-let-7 and pre-let-7) to control their maturation, including TRBP, Lin28 (Lin28A and Lin28B), Musashi1, TUT4, hnRNPA1 and KHSRP proteins. However, much remains to be known about the mechanistic details of these interactions and how they regulate miRNA maturation. The long-term objective of our research program is to gain a detailed understanding of specific mechanisms that regulate let-7 miRNA maturation. Our working hypothesis is that miRNA maturation requires a complex interplay of protein/protein and protein/RNA interactions that target the pri- and pre-miRNAs to either stimulate or repress the activity of the two main miRNA processing enzymes, Drosha and Dicer. Our current focus is on a subset of proteins known to play critical functions in the regulation of let-7 miRNA levels. In the next five years, we will characterize the mechanistic details by which these proteins regulate the maturation of the let-7 miRNAs at both the molecular and atomic levels. Our work will involve biochemical, biophysical and structural characterization of select protein/protein and protein/RNA complexes that regulate the Dicer and/or Drosha cleavage steps of miRNA maturation. Our studies will provide critical and timely insights into our understanding of miRNA maturation and how miRNA levels are controlled. In addition, given that miRNAs have enormous potential for medical and agricultural applications, our basic research will provide crucial information needed to help evaluate and exploit these new cutting-edge applications.

MicroRNAs （miRNAs）作为rna诱导沉默复合体（RISC）的一部分，通过序列互补识别信使rna (mRNA)，在基因表达调控中发挥重要作用。通常，通过形成mirna引导的RISC靶向mRNA会导致mRNA的翻译停滞和降解。在人类中，基因组编码大约2000个mirna，它们有可能调节60%以上的mrna。miRNA水平的错误调控可以改变基因表达模式，而这些变化与发育缺陷和几种人类疾病直接相关。