Analysis of an Active Deformylation Mechanism of 5-Formyldeoxycytidine (fdC) in Stem Cells

Schön, Alexander; Kaminska, Ewelina; Schelter, Florian; Ponkkonen, Eveliina; Schiffers, Sarah und Carell, Thomas (30. Januar 2020): Analysis of an Active Deformylation Mechanism of 5-Formyldeoxycytidine (fdC) in Stem Cells. In: Angewandte Chemie International Edition, Bd. 59, Nr. 14: S. 5591-5594

Abstract

The removal of 5-methyl-deoxycytidine (mdC) from promoter elements is associated with reactivation of the silenced corresponding genes. It takes place through an active demethylation process involving the oxidation of mdC to 5-hydroxymethyl-deoxycytidine (hmdC) and further on to 5-formyl-deoxycytidine (fdC) and 5-carboxy-deoxycytidine (cadC) with the help of a-ketoglutarate-dependent Tet oxygenases. The next step can occur through the action of a glycosylase (TDG), which cleaves fdC out of the genome for replacement by dC. A second pathway is proposed to involve C-C bond cleavage that converts fdC directly into dC. A 6-aza-5-formyl-deoxycytidine (a-fdC) probe molecule was synthesized and fed to various somatic cell lines and induced mouse embryonic stem cells, together with a 2’-fluorinated fdC analogue (F-fdC). While deformylation of F-fdC was clearly observed in vivo, it did not occur with a-fdC, thus suggesting that the C-C bond-cleaving deformylation is initiated by nucleophilic activation.

• Dokumententyp: Zeitschriftenartikel
• EU Funded Grant Agreement Number: 741912
• EU-Projekte: Horizon 2020 > ERC Grants > ERC Advanced Grant > ERC Grant 741912: EPiR - The Chemical Basis of RNA Epigenetics
• Publikationsform: Publisher's Version
• Keywords: demethylation; DNA modifications; epigenetics; formylcytidine
• Fakultät: Chemie und Pharmazie > Department Chemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1521-3773
• Sprache: Englisch

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