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Subcellular mRNA Localization Regulates Ribosome Biogenesis In Migrating Cells

44 Pages Posted: 28 Jan 2020 Sneak Peek Status: Under Review

See all articles by Maria Dermit

Maria Dermit

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology

Martin Dodel

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology

Flora Lee

Francis Crick Institute

Muhammad S. Azman

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology

Hagen Schwenzer

University of Oxford - Department of Oncology

J. Louise Jones

Queen Mary University of London - Centre for Tumour Biology

Sarah P. Blagden

University of Oxford - Department of Oncology

Jernej Ule

University of Cambridge - MRC Laboratory of Molecular Biology; Francis Crick Institute

Faraz K. Mardakheh

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology

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Abstract

Translation of Ribosomal Protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms which modulate RP-mRNA translation in coordination with other cellular processes are poorly defined. Here we show that the subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich protrusive fronts of the cells. This localization is mediated by La-related protein 6 (LARP6), an RNA binding protein that is enriched in protrusions. Protrusions act as hotspots of translation for RP-mRNAs, resulting in enhancement of RP synthesis, ribosome biogenesis, and overall protein synthetic capacity of migratory cells, required for supporting efficient migration and proliferation. In human breast carcinomas, Epithelial to Mesenchymal Transition (EMT) upregulates LARP6 expression to enhance protein synthesis and support invasive growth. Our findings reveal LARP6 mediated mRNA localization as a key regulator of ribosome biogenesis during cell migration, and demonstrate a role for this process in cancer progression downstream of EMT.

Keywords: RNA localization, local translation, ribosome biogenesis, mTORC1, LARP1, LARP6, translation, Cell Migration, invasion, EMT

Suggested Citation

Dermit, Maria and Dodel, Martin and Lee, Flora and Azman, Muhammad S. and Schwenzer, Hagen and Jones, J. Louise and Blagden, Sarah P. and Ule, Jernej and Mardakheh, Faraz K., Subcellular mRNA Localization Regulates Ribosome Biogenesis In Migrating Cells. Available at SSRN: https://ssrn.com/abstract=3525553 or http://dx.doi.org/10.2139/ssrn.3525553
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Maria Dermit

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology ( email )

United Kingdom

Martin Dodel

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology ( email )

United Kingdom

Flora Lee

Francis Crick Institute ( email )

1 Midland Road
London, NW1 1AT
United Kingdom

Muhammad S. Azman

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology ( email )

United Kingdom

Hagen Schwenzer

University of Oxford - Department of Oncology ( email )

Old Road Campus Research Building
Roosevelt Drive
Oxford, OX3 7DQ
United Kingdom

J. Louise Jones

Queen Mary University of London - Centre for Tumour Biology ( email )

United Kingdom

Sarah P. Blagden

University of Oxford - Department of Oncology ( email )

Old Road Campus Research Building
Roosevelt Drive
Oxford, OX3 7DQ
United Kingdom

Jernej Ule

University of Cambridge - MRC Laboratory of Molecular Biology ( email )

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Francis Crick Institute ( email )

1 Midland Road
London, NW1 1AT
United Kingdom

Faraz K. Mardakheh (Contact Author)

Queen Mary University of London - Centre for Cancer Cell and Molecular Biology ( email )

United Kingdom

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