Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine DNA glycosylase

摘要

Thymine DNA glycosylase (TDG) is an essential multifunctional enzyme involved in DNA base excision repair, DNA demethylation, and transcription regulation. TDG is the predominant enzyme to remove thymine from T/G mispair, which arises due to deamination of 5-methylcytosine at the CpG dinucleotide, thereby preventing C to T mutations. SIRT1 is a member of class III NAD⁺-dependent histone/protein deacetylases. In this study, we demonstrate that SIRT1 interacts with the residues 67–110 of human TDG (hTDG). In addition, SIRT1 enhances TDG glycosylase activity and deacetylates acetylated TDG. TDG acetylation weakens its interaction with SIRT1. Although acetylated TDG has reduced glycosylase activity toward T/G, 5-formylcytosine/G, and 5-carboxylcytosine/G, it has a stronger activity toward 5-fluorouracil/G substrate as compared to unmodified TDG. SIRT1 weakly stimulates acetylated hTDG activity toward T/G, 5-formylcytosine/G, and 5-carboxylcytosine/G as compared to control hTDG. Sirt1 knockout mouse embryonic fibroblast cells have higher levels of TDG expression and acetylation. The physical and functional interactions between SIRT1 and TDG may mediate DNA repair, gene expression, and FU-mediated cytotoxicity.