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Schön, Alexander; Kaminska, Ewelina; Schelter, Florian; Ponkkonen, Eveliina; Schiffers, Sarah; Carell, Thomas ORCID: 0000-0001-7898-2831 (30. January 2020): Analysis of an Active Deformylation Mechanism of 5-Formyldeoxycytidine (fdC) in Stem Cells. In: Angewandte Chemie International Edition, Vol. 59, No. 14: pp. 5591-5594
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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.