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

• Published in: Biochemical journal Vol. 456; no. 1; p. 89
• Main Authors: Madabushi, Amrita, Hwang, Bor-Jang, Jin, Jin, Lu, A-Lien
• Format: Journal Article
• Language: English
• Published: England 15.11.2013
• Subjects: Acetylation; Animals; Antineoplastic Agents - chemistry; DNA Repair; Fibroblasts - metabolism; Fluorouracil - chemistry; HEK293 Cells; Humans; Mice; Mice, Knockout; Sirtuin 1 - chemistry; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Substrate Specificity; Thymine DNA Glycosylase - chemistry; Thymine DNA Glycosylase - metabolism
• ISSN: 1470-8728
• DOI: 10.1042/BJ20130670

TDG (thymine DNA glycosylase) is an essential multifunctional enzyme involved in DNA base excision repair, DNA demethylation and transcription regulation. TDG is the predominant enzyme that removes thymine from T/G mispair, which arises due to deamination of 5-methyl-cytosine at the CpG dinucleotide, thereby preventing C to T mutations. SIRT1 is a member of class III NAD+-dependent histone/protein deacetylases. In the present study, we demonstrate that SIRT1 interacts with residues 67-110 of hTDG (human TDG). 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 towards T/G, 5-formylcytosine/G and 5-carboxylcytosine/G, it has a stronger activity towards a 5-fluorouracil/G substrate as compared with unmodified TDG. SIRT1 weakly stimulates acetylated hTDG activity towards T/G, 5-formylcytosine/G and 5-carboxylcytosine/G as compared with 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 (5-fluorouracil)-mediated cytotoxicity.