Published on June 1, 2019 in Nat Commun volume 10, 1.
PubMed ID: 31186410
The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (mC) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of mC 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\xa0a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for mC in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.