Metabolic Aspects of Epigenome: Coupling of S-Adenosylmethionine Synthesis and Gene Regulation on Chromatin by SAMIT Module
Histone and DNA methyltransferases utilize S-adenosyl-L-methionine (SAM), a key intermediate of sulfur amino acid metabolism, as a donor of methyl group. SAM is biosynthesized by methionine adenosyltransferase (MAT) using two substrates, methionine and ATP. Three distinct forms of MAT (MATI, MATII and MATIII), encoded by two distinct genes (MAT1A and MAT2A), have been identified in mammals. MATII consists of α2 catalytic subunit encoded by MAT2A and β regulatory subunit encoded by MAT2B, but the physiological function of the β subunit is not clear. MafK is a member of Maf oncoproteins and functions as both transcription activator and repressor by forming diverse heterodimers to bind to DNA elements termed Maf recognition elements. Proteomics analysis of MafK-interactome revealed its interaction with both MATIIα and MATIIβ. They are recruited specifically to MafK target genes and are required for their repression by MafK and its partner Bach1. Because the catalytic activity of MATIIα is required for the MafK target gene repression, MATIIα is suggested to provide SAM locally on chromatin where it is recruited. One of the unexpected features of MATII is that MATIIα interacts with many chromatin-related proteins of diverse functions such as histone modification, chromatin remodeling, transcription regulation, and nucleo-cytoplasmic transport. MATIIα appears to generate multiple, heterogenous regulatory complexes where it provides SAM. Considering their function, the heterooligomer of MATIIα and β is named SAMIT (SAM-integrating transcription) module within their interactome where it serves SAM for nuclear methyltransferases.
KeywordsHistone Acetylation Histone Methylation Nuclear Compartment Acute Myeloid Leukemia Cell Line Methionine Adenosyltransferase
- Brown JM, Ball JG, Hogsett A, Williams T, Valentovic M (2010) Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity. Toxicol Appl Pharmacol 247(1):1–9PubMedCrossRefGoogle Scholar
- Cantoni GL (1953) S-adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J Biol Chem 204:403–416Google Scholar