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Biochemical and CryoEM studies of spliceosome activation.

Objective

Pre-mRNA splicing is a fundamental maturation step of eukaryotic mRNAs that consists of the removal of introns and the concomitant ligation of exons by two successive transesterification reactions. This complex biological process is catalyzed by the spliceosome, a gigantic ribonucleoprotein particle that assembles de novo on each intron and uses a single RNA-based active site to perform both reactions.
The spliceosome is composed of five snRNPs (U1, U2, U4, U5, U6) that are recruited to pre-mRNAs in a stepwise manner. When a pre-catalytic spliceosome, consisting of all five snRNPs, is formed on a pre-mRNA it has no pre-existing active site and undergoes extensive compositional and conformational changes to become “catalytically competent”. During this transition, two snRNPs (U1 and U4) are lost and several new factors are recruited, ensuring the formation and stabilization of the active site as well as the correct positioning of the pre-mRNA’s reactive groups in the catalytic centre.
Thanks to recent technological advances in Electron Microscopy (EM), a series of cryoEM structures of fully assembled “active” spliceosomes at atomic resolution have been solved in the host group and elsewhere, in the past two years. These structures, which have created much excitement in the RNA community, visualize the spliceosome during each step of the catalytic cycle and allow a mechanistic understanding of catalysis. However, due to the scarcity of high-resolution information on earlier complexes, many questions remain regarding spliceosome activation.
My project aims at filling a gap in our understanding of pre-mRNA splicing by unraveling the molecular details of spliceosome activation. To that end, I will use a combination of biochemical characterization and cryoEM to study yeast spliceosome captured at discrete early stages of activation.
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Coordinator

UNITED KINGDOM RESEARCH AND INNOVATION

Address

Polaris House North Star Avenue
Sn2 1fl Swindon

United Kingdom

Activity type

Research Organisations

EU Contribution

€ 195 454,80

MEDICAL RESEARCH COUNCIL

Address

North Star Avenue Polaris House 2 Floor David Phillips Building
Sn2 1fl Swindon

United Kingdom

Activity type

Research Organisations

Project information

Grant agreement ID: 795732

Status

Ongoing project

  • Start date

    1 March 2019

  • End date

    28 February 2021

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 195 454,80

  • EU contribution

    € 195 454,80

Coordinated by:

UNITED KINGDOM RESEARCH AND INNOVATION

United Kingdom