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Biogenesis of Oncogenic MicroRNAs : from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes

Biogenesis of Oncogenic MicroRNAs : from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes

Objective

Micro-RNAs are a recently identified class of small non-coding RNAs that have been shown to regulate the expression of up to 30% of human genes. The contribution of miRNAs in gene regulation is gaining considerable attention, particularly given the growing links between miRNA mis-function or expression and disease. Certain miRNAs have been demonstrated to display oncogenic-like phenotypic effects and their overexpression is heavily implicated in the development of cancers. MiRNAs mature via a two-step pathway involving two processing complexes: first Drosha-DCGR8 and second Dicer-PACT-TRBP. The two ribonucleases Drosha and Dicer are recruited by multi-domain RNA-binding accessory proteins that interact with specific, but currently unknown, structural features present in immature miRNAs. In this project I propose to perform an ambitious and comprehensive multidisciplinary analysis of biomolecular interaction networks involved in human miRNA biogenesis. An automated molecular biology approach will be employed to rapidly clone, express and screen soluble domains derived from each modular processing protein. I will use the latest fast NMR methods to rapidly assess protein and RNA folds, and protein and RNA interaction sites. These results will define the roles of each biogenesis protein, describe RNA recognition mechanisms and reveal the first atomic resolution picture of miRNA processing complexes. This structural evaluation will form the basis for the design and testing of inhibitors of miRNA biogenesis. Over-expression of oncogenic miRNAs correlates well with cancer. I propose to evaluate the possibility of using anti-sense oligonucleotides to block the regions of the immature miRNA recognized by the biogenesis machinery. The efficacy of these molecules will be explored in vivo with the view to developing innovative ways of probing miRNA function or potential new cancer therapies.
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Coordinator

COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES

Address

Rue Leblanc 25
75015 Paris 15

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 75 000

Administrative Contact

Eva Pebay-Peyroula (Prof.)

Project information

Grant agreement ID: 231082

Status

Closed project

  • Start date

    1 September 2008

  • End date

    31 August 2011

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 75 000

  • EU contribution

    € 75 000

Coordinated by:

COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES

France