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| Home > Publications database > 5-Formylcytosine is not a prevalent RNA modification in mammalian cells. |
| Home > Publications database > 5-Formylcytosine is not a prevalent RNA modification in mammalian cells. |
| Journal Article | DKFZ-2025-02422 |
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2025
Springer Nature
[London]
Abstract: The RNA modification 5-formylcytidine (f5C) is poorly explored in mammals. Low f5C levels reported in mRNA may reflect spurious 5-methylcytidine (m5C) oxidation or targeted demethylation by TET or ALKBH1 dioxygenases. We analyzed f5C in RNA of mouse embryonic stem cells (mESCs) using LC-MS/MS and chemical-assisted sequencing. We reveal that the previously reported pyridine-borane-sequencing misidentifies N4-acetylcytidine (ac4C) and unmodified, hyper-reactive cytidines in a CUMC context as f5C. To overcome these limitations, we developed FIBo-seq with enhanced specificity and sensitivity for f5C-sequencing. We find no evidence for a role of TET enzymes in generating f5C, unlike for ALKBH1. Moreover, no f5C sites are detectable in mRNA. Instead, the bulk of mammalian f5C resides in the well-established mitochondrial tRNA Methionine (mt-tRNAMet) and is mediated by ALKBH1. The results argue against an instructive function for f5C outside tRNA in mammals.
Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Cytosine: analogs & derivatives (MeSH) ; Cytosine: metabolism (MeSH) ; Cytidine: analogs & derivatives (MeSH) ; Cytidine: metabolism (MeSH) ; AlkB Homolog 1, Histone H2a Dioxygenase: metabolism (MeSH) ; AlkB Homolog 1, Histone H2a Dioxygenase: genetics (MeSH) ; Mouse Embryonic Stem Cells: metabolism (MeSH) ; RNA, Messenger: metabolism (MeSH) ; RNA, Messenger: genetics (MeSH) ; RNA, Transfer, Met: metabolism (MeSH) ; RNA, Transfer, Met: genetics (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Proto-Oncogene Proteins: genetics (MeSH) ; RNA: metabolism (MeSH) ; RNA Processing, Post-Transcriptional (MeSH) ; Tandem Mass Spectrometry (MeSH) ; DNA-Binding Proteins (MeSH) ; Cytosine ; Cytidine ; 5-formylcytosine ; AlkB Homolog 1, Histone H2a Dioxygenase ; RNA, Messenger ; RNA, Transfer, Met ; Alkbh1 protein, mouse ; Proto-Oncogene Proteins ; RNA ; N-acetylcytidine ; TET1 protein, mouse ; DNA-Binding Proteins
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