S-adenosylhomocysteine Hydrolase Participates in DNA Methylation Inheritance

J Mol Biol. 2018 Jul 6;430(14):2051-2065. doi: 10.1016/j.jmb.2018.05.014. Epub 2018 May 28.

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.

Keywords: AdoHcy; DNMT1; SAHH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase / genetics
  • Adenosylhomocysteinase / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA Methylation*
  • DNA Replication
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Metabolic Networks and Pathways
  • Mutation
  • Proteomics / methods*
  • Repetitive Sequences, Nucleic Acid
  • S Phase
  • S-Adenosylhomocysteine / metabolism*
  • Signal Transduction

Substances

  • S-Adenosylhomocysteine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • AHCY protein, human
  • Adenosylhomocysteinase