S-adenosylhomocysteine Hydrolase Participates in DNA Methylation Inheritance |
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Authors: | VK Chaithanya Ponnaluri Pierre-Olivier Estève Cristian I Ruse Sriharsa Pradhan |
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Institution: | New England Biolabs Inc, 240 County Road, Ipswich, MA 01938, USA |
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Abstract: | DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-l-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-l-homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA-mediated knockdown resulted in hypomethylation of the genome. Hypermethylation was consistent in both gene bodies and repetitive DNA elements leading to aberrant gene regulation. Cells overexpressing SAHH specifically up-regulated metabolic pathway genes and down-regulated PPAR and MAPK signaling pathways genes. Therefore, we suggest that alteration of SAHH level affects global DNA methylation levels and gene expression. |
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Keywords: | SAHH DNMT1 AdoHcy DNMT1 DNA (cytosine-5) methyltransferase 1 SAHH AdoMet 5mC 5-methylcytosine ES embryonic stem AdoHcy AP adenosine periodate WGBS whole-genome bisulfite sequencing DMRs differentially methylated regions |
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