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Mechanisms of human mRNA packaging and export

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.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/molecular biology/structural biology

Call for proposal

ERC-2020-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Address
Campus-vienna-biocenter 1
1030 Wien
Austria
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 1 500 000

Beneficiaries (1)

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Austria
EU contribution
€ 1 500 000
Address
Campus-vienna-biocenter 1
1030 Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)