Control of protein synthesis through mRNA pseudouridylation by dyskerin

Science Advances · 10 authors, 9 centres

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TL;DR

This study demonstrates that the enzyme dyskerin modifies mRNA with pseudouridine, which reduces the translation efficiency of those mRNAs into protein. The process is cotranscriptional and is implicated in the pathogenesis of dyskeratosis congenita.

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The authors investigated the role of dyskerin, a pseudouridine synthase, in mRNA modification. Using human cell lines, they found that dyskerin associates with RNA polymerase II and modifies thousands of mRNAs co-transcriptionally in chromatin. Depletion of dyskerin reduced mRNA pseudouridylation and enhanced global protein synthesis by approximately 40%, while reintroduction of wild-type dyskerin normalized translation. The study proposes that mRNA pseudouridylation by dyskerin is a mechanism to attenuate translation, with implications for normal development and disease.

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other

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preclinical research

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ORIGINAL PAPER

PMC10381945

Control of protein synthesis through mRNA pseudouridylation by dyskerin

Science Advances

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ABSTRACT

Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1 ). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.

CITATION EXPORT

Chiara Pederiva, Davide M. Trevisan, Dimitra Peirasmaki et al.. Control of protein synthesis through mRNA pseudouridylation by dyskerin. Science Advances. (2023). https://doi.org/10.1126/sciadv.adg1805

AUTHORS

10 · 9 CENTRES

Chiara Pederiva, Davide M. Trevisan, Dimitra Peirasmaki, Shan Chen, Sharon A. Savage, Ola Larsson, Jernej Ule, Laura Baranello, Federico Agostini, Marianne Farnebo

1Department of Cell and Molecular Biology, Karolinska Institutet, Solna 17165, Sweden.
2Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14152, Sweden.
3Department of Oncology and Pathology, Karolinska Institutet, Solna 17165, Sweden.
4Science for Life Laboratory, Stockholm 17165, Sweden.
5Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20852, USA.
6The Francis Crick Institute, London NW1 1AT, UK.
7UK Dementia Research Institute, King’s College London, London W1T 7NF, UK.
8National Institute of Chemistry, 1001 Ljubljana, Slovenia.
9Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna 17165, Sweden.