Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10020-7
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Funding
- Cancer Research UK (CR-UK)
- European Research Council (ERC)
- Wellcome
- MRC
- Wellcome Trust Senior Research Fellowship [084229]
- MRC Career Development Award [G10000564]
- Wellcome Trust Seed Award [210144/Z/18/Z]
- Wellcome Trust Centre for Cell Biology Core Grants [077707, 092076]
- University of Tabuk
- Khalifa University of Science and Technology Faculty start up award [FSU 2018 01]
- Wellcome Trust PhD Programme in Stem Cell Biology Medicine
- Wellcome Trust [210144/Z/18/Z] Funding Source: Wellcome Trust
- MRC [G1000564] Funding Source: UKRI
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The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m(5)C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m(5)C deposition into the abundant non-coding vault RNA VTRNA1.1. Methylation of cytosine 69 in VTRNA1.1 occurs frequently in human cells, is exclusively mediated by NSUN2, and determines the processing of VTRNA1.1 into small-vault RNAs (svRNAs). We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein that counteracts VTRNA1.1 processing by binding the non-methylated form with higher affinity. Both NSUN2 and SRSF2 orchestrate the production of distinct svRNAs. Finally, we discover a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for m(5)C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.
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