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

Autor: Alexander Schön, Eva Korytiaková, Florian Schelter, Thomas Carell, Sarah Schiffers, Ewelina Kaminska, Eveliina Ponkkonen
Rok vydání: 2020
Předmět:
Zdroj: Angewandte Chemie (International Ed. in English)
Angewandte Chemie International Edition
ISSN: 1521-3773
Popis: 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 α‐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.
Please release Me, let Me go: The demethylation process of 5‐methyl‐deoxycytidine (mdC), which is associated with the reactivation of silenced genes, was investigated. In the course of active demethylation in stem cells, mdC is oxidized to 5‐formyl‐deoxycytidine (fdC), which is then deformylated, potentially after addition of a nucleophile at the C6‐position.
Databáze: OpenAIRE
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