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New paper in Nature Communications

Dr Gracjan Michlewski has published a paper in Nature Communications - "Loss of 5-methylcytosine alters the biogenesis of Vault-derived small RNAs to coordinate epidermal differentiation".

Abstract

The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m5C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m5C 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 m5C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.

Significance:

Summary of VTRNA1.1 processing into svRNA4. A) Expression of both NSUN2 and SRSF2 (e.g. in progenitor cells) result in high levels of VTRNA1.1 methylation (CH3 – m5C) and high levels of svRNA4 and repressed differentiation. B) No NSUN2 in the presence of SRSF2 suppresses formation of svRNA4 and allows differentiation. C) Lack of expression of both NSUN2 and SRSF2 release VTRNA1.1 from SRSF2 binding and increases the levels of svRNA4.
Summary of VTRNA1.1 processing into svRNA4. A) Expression of both NSUN2 and SRSF2 (e.g. in progenitor cells) result in high levels of VTRNA1.1 methylation (CH3 – m5C) and high levels of svRNA4 and repressed differentiation. B) No NSUN2 in the presence of SRSF2 suppresses formation of svRNA4 and allows differentiation. C) Lack of expression of both NSUN2 and SRSF2 release VTRNA1.1 from SRSF2 binding and increases the levels of svRNA4.

This study is important as m5C modification in RNA is very common. However, it is largely unknown what are the functional consequences in terms of molecular mechanisms as well as cellular and organismal functions of this RNA modification.

Further information

Link to journal article in Nature Communications

Dr Gracjan Michlewski's lab profile

Infection Medicine website

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