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PreprintCited by 0RNA Research and SplicingRNA modifications and cancerRNA regulation and disease

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TET dioxygenases localize at splicing speckles and promote RNA splicing

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Hastert, Florian D., Weber, Jasmin, Bauer, Christina, Zhadan, Andreas, Singh, Deepanshu N.D., Dix, Thomas C., Arnold, Roland, Bessonov, Sergey, Soller, Matthias, Leonhardt, Heinrich, Cardoso, M. Cristina, Arroyo, Maria·2025·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2025.03.07.641893

Preprint — published as 10.1080/19491034.2025.2536902 · Paper page

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Abstract

The dynamic regulation of RNA metabolism plays a crucial part in cellular function, with emerging evidence suggesting an important role for RNA modifications in this process. This study explores the relationship between RNA splicing and the TET dioxygenase activity, shedding light on the role of hm5C (RNA 5-hydroxymethylcytosine), and TET proteins, in RNA metabolism. Integrating data from mass spectrometry, AlphaFold structural modeling, microscopic analysis, and different functional assays including in vitro splicing, TET proteins were found to regulate splicing. We show that TET1, TET2, and TET3 interact with the splicing factors U2AF1 and U2AF2. Interestingly, TET dioxygenases localize in splicing speckles in mammalian and Drosophila cells. TET speckles association is RNA dependent, as it is TET interaction with splicing factors. Furthermore, in vitro splicing assays revealed that all three TET proteins promote splicing efficiency, and the oxidation of m5C to hm5C can restore splicing efficiency in vitro. The latter highlights the regulatory role of cytosine modifications in RNA metabolism. These findings provide insights into the complex interplay between RNA modifications and splicing, suggesting a multifaceted role for TET proteins in RNA metabolism beyond its canonical DNA demethylation function. Graphical abstract: Highlights: – TET1 localizes in splicing speckles in an RNA-dependent manner – TET proteins, especially TET1, interact with the splicing factors U2AF1 and U2AF2 – TET proteins increase splicing efficiency, independent of their catalytic activity – RNA 5-methylcytosine (m5C) oxidation to 5-hydroxymethylcytosine (hm5C) restores splicing efficiently in vitro

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Metadata

Authors
Hastert, F. D., Weber, J., Bauer, C., Zhadan, A., Singh, D. N. D., Dix, T. C., Arnold, R., Bessonov, S., Soller, M., Leonhardt, H., Cardoso, M. C., & Arroyo, M.
Affiliations
  • Technische Universität Darmstadt (DE)
  • Ludwig-Maximilians-Universität München (DE)
  • University of Birmingham (GB)
  • Max Planck Institute for Multidisciplinary Sciences (DE)
Corresponding author
Arroyo, Maria
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2025-03-11
DOI
10.1101/2025.03.07.641893
OpenAlex
W4408312209
Cited by
0
References
2
Type
posted content
Language
en
Open access
Licence
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by-nc)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
TET enzymes, RNA splicing, nuclear speckles, 5-hydroxymethylcytosine, U2AF1, U2AF2, RNA modification, RNA metabolism, TET1, TET2, TET3

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