MIRNA MECHANISM

In-vitro system for mammalian miRNA function

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 Obiettivo del progetto (Objective)

'Over the past decade, micro (mi) RNAs have emerged as key regulators of gene expression. Many miRNAs have been linked to diseases, such as cancer or diabetes. MiRNAs bind to specific sequences in the 3’-untranslated region (UTR) of mRNAs, thereby causing inhibition of translation and/or mRNA degradation. However, the detailed molecular mechanism and the factors involved in miRNA-mediated gene silencing are still incompletely understood. The primary research objective of the current proposal is the generation of a novel mammalian in-vitro system that will allow a detailed biochemical dissection of the molecular mechanisms underlying medical relevant miRNA-guided gene silencing. In particular, we will characterize repression mediated by the tumorsuppressor miRNA let-7. We will elucidate the role of cis- and trans-acting factors in miRNA mediated repression and use the system to purify native miRISC-RNP-complexes (Ribonucleoprotein-complexes) and subsequently identify and characterize the components of the complex. Thus, the knowledge gained from this proposal will enhance our understanding of miRNA function and provide novel insights into the role of RNA metabolism in disease, which will be applicable to the development of novel diagnostic and therapeutic strategies targeting miRNA-associated pathologies.'

Introduzione (Teaser)

The key to treating or preventing diseases in the future could entail the repression of the implicated genes. EU research is looking at the potential role of a group of small molecules called microRNAs (miRNAs).

Descrizione progetto (Article)

Genes are expressed or transcribed to produce a protein. Messenger RNA (mRNA) passes this code from the DNA to the ribosomes for protein assembly. Many molecules including miRNAs can interfere with this process and repress gene translation through mRNA degradation by removal of adenyl groups (deadenylation).

Unravelling the underlying mechanisms could help in the development of therapeutic tools that selectively disable the production of proteins involved in disease development. Researchers in the 'In-vitro system for mammalian miRNA function' (MIRNA MECHANISM) project have analysed how miRNAs act by manipulating the biochemistry of the gene transcription system extracted from the fruit fly Drosophila.

The scientists showed that if mRNA has a poly(A) tail composed of many adenyl groups joined together in a polymer fashion, the repression is more effective. The poly(A)-binding protein (PABP) mediates the extent of gene silencing.

The researchers looked at the whole miRNA-mediated silencing complex (miRISC) and mapped the proteins responsible. They found that PABP actually acts as a co-repressor of gene translation and that the longer the poly (A) tail, the stronger the inhibition. This finding overturns current models that propose that miRISC interferes with a positive function in PABP in translation.

The results of the MIRNA MECHANISM project have wide-ranging significance for disease control and human health. miRNAs are implicated in diseases such as cancer and diabetes. Information on the action and structure of these molecular players is vital for the development of designer drugs to silence the genes behind chronic ill-health.