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Mechanisms of human mRNA packaging and export

Project description

Dissecting the mechanism of mRNA export from the nucleus

Transport in and out of the nucleus is a highly selective process carried out by a specific set of proteins. In terms of mRNA, it must undergo full processing and maturation in the nucleus before crossing the nuclear envelope. The EU-funded RNApaxport project aims to shed light on the mechanism of this mRNA transport specificity. In particular, scientists will investigate how a defined set of conserved proteins package and export all nuclear mRNA. For this purpose, they will examine the organisation, dynamics and function of key packaging factors. Insight into the role of mRNA length and sequence will help understand the complex mechanisms of gene expression.

Objective

Eukaryotic gene expression is partitioned across two cellular compartments: the nucleus, where messenger RNA (mRNA) is produced, and the cytoplasm, where protein translation occurs. mRNA export across the nuclear membrane is highly selective, ensuring that only fully processed and mature mRNA is transported to the cytoplasm. Yet how does the multi-step mRNA maturation process converge to a binary decision, ‘to export or not to export’? While we know many of the proteins involved in packaging and export of nuclear mRNA ribonucleoprotein complexes (mRNPs), how a defined set of conserved proteins package and export all nuclear mRNA remains poorly understood. To reveal how specificity towards mature mRNA is achieved and to identify regulatory checkpoints, I propose to visualize key mRNP intermediates using a state-of-the-art integrative structural biology approach. First, we will determine the human THO/TREX complex structure to reveal how this key packaging factor is organized and brought to mRNA (aim 1). Second, we will determine the structure of a human mRNP 5’-end to explain how two key features of mature mRNPs, the 5’-cap and the first splice junction, are recognized and integrated by THO/TREX to achieve export competence (aim 2). Third, we will obtain the architecture of endogenous human mRNPs to reveal their dynamics and to determine how mRNAs of varied length and sequence are packaged (aim 3). These data will enable the complementary and targeted in vitro and in vivo structure-function analysis. Taken together, the expected results will reveal novel insights into the mechanisms that underlie an important step of gene expression, which mediates nuclear mRNA quality control and links transcription to translation. My background in structural biology, mRNA transcription and processing is ideally suited to carry out this high-impact proposal.

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Coordinator

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Net EU contribution
€ 1 500 000,00
Address
Campus-vienna-biocenter 1
1030 Wien
Austria

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Region
Ostösterreich Wien Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
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Other funding
€ 0,00

Beneficiaries (1)