MICRORNA EXPORT

Structural and biophysical mechanism of microRNA nuclear export

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 Obiettivo del progetto (Objective)

'MicroRNAs are a recently discovered class of small non-coding RNAs that act as post-transcriptional regulators of gene expression by silencing target mRNAs. They have wide ranging roles in many cellular processes including cellular proliferation, stress response, apoptosis, development and differentiation. Altered expression of microRNA has been implicated in tumorigenesis, and microRNAs are recognised as modulating factors in numerous cancers including gastric cancer, lung cancer and lymphocytic leukaemia. Specifically, microRNA functions within the cytoplasm in concert with the human-induced silencing complex by binding the 3’ untranslated region of the target mRNA. This binding to target mRNA effectively inhibits expression of the protein, and thus mediates the gene silencing effect of microRNA. This project aims to elucidate the structure and biophysical basis of the nuclear export complex formed by pre-microRNA (precursor of microRNA), RanGTP and exportin-5. These goals will be achieved using a combination of structural, biochemical and biophysical approaches. X-ray crystallography and nuclear magnetic resonance will be utilised to study the structure of the export complex of microRNA. In parallel with the determination of the complex structure, the key residues involved in complex formation will be identified by mutagenesis, cross-linking and further NMR approaches. Furthermore, a range of biophysical techniques will be employed to study the thermodynamic and kinetic basis for the formation of the microRNA export complex. The information provided by this study will be of the highest international standard and will open novel avenues to therapeutic design as well as represent a significant advance in our understanding of cellular biology. Importantly, it will provide a platform for knowledge sharing and collaboration between a European based organization and a top-class non European researcher.'

Introduzione (Teaser)

MicroRNAs play many roles in a variety of cellular processes affecting our genes. An alteration in their expression has been implicated in the production of tumours.

Descrizione progetto (Article)

RNA, or ribonucleic acid, is a chain of molecules that works together with DNA. And as most of us know by now, DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. It makes us what and who we are.

MicroRNAs belong to a class of small non-coding RNAs that regulate gene expression by acting on target messenger RNAs (mRNAs). They are present in cellular proliferation, stress response, apoptosis, development and differentiation. However, when their own expression is disturbed they are seen as modulating factors in diseases such as gastric cancer, lung cancer and lymphocytic leukaemia.

The EU-funded project 'Structural and biophysical mechanism of microRNA nuclear export' (MicroRNA Export) used a combination of structural, biochemical and biophysical approaches as well as X-ray crystallography and nuclear magnetic resonance to study the structure and biophysical properties of the nuclear export complex of microRNA.

Integrating all the steps along a gene expression pathway involves a complex network of interactions. For a particular group of genes, this integration process, essential to the gene expression pathway, is termed 'gene-gating'. Project researchers have worked to understand the biological process of gene-gating at a molecular level. Earlier experiments using novel-binding assays gave a boost for this work to investigate the structure and function of the small nuclear localised protein Sus1 in gene-gating. Results from this body of research have been published in the Journal of Biological Chemistry.

Although initial results suggested Sus1to be the structural and functional key in the gene-gating process, further work suggested it is just a component of separate sub-complexes rather than a single chain linking the two complexes. This has helped the researchers to understand how the SAGA and TREX-2 complexes are involved in gene-gating.