title: S-Adenosylhomocysteine enhances DNA damage through increased β-amyloid formation and inhibition of the DNA-repair enzyme OGG1b in microglial BV-2 cells.
abstract: S-Adenosylhomocysteine (SAH) is a risk factor for neurodegenerative diseases such as Alzheimer's disease, for which β-Amyliod (Aβ) formation is a major risk factor. We recently showed that SAH increases Aβ formation in mouse microglial BV2 cells. Here, we show that incubation of BV2 cells with SAH (0-500nM) for 6-24h sequentially increased Aβ formation, ROS and DNA damage measured as 8-oxo-deoxyguanosine (8-oxo-dG) levels. Pre-incubation of BV2 cells with 20μM β-secretase inhibitor IV for 30min followed by incubation with SAH (500nM) markedly decreased Aβ formation and 8-oxo-dG levels. Treatment with SAH for 24h concentration-dependently inhibited DNA methyltransferase (DNMT1) activity and inhibited DNMT1 binding to Sp1 site of 8-oxoG-DNA glycosylases I (OGG1) promoter and OGG1 protein and mRNA expression at 24h; the latter effect was attributed to hypomethylation of the OGG1 gene promoter, because pre-incubation of cells with betaine (1.0mM for 30 min) markedly prevented the inhibition of OGG1 protein expression induced by SAH. Overall, we demonstrate that SAH increases DNA damage in BV-2 cells possible by increased Aβ formation leading to increased formation of ROS. Furthermore, the DNA damage is enhanced by SAH through inhibition of DNMT1 activity and hypomethylation of OGG1 gene promoter.
authors: Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung, 402, Taiwan.
authors: Hung-Chi
authors: HC
authors: Lin
authors: Tuzz-Ying
authors: TY
authors: Song
authors: Miao-Lin
authors: ML
authors: Hu
mesh_terms: D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D012435:S-Adenosylhomocysteine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse