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Cytoplasmic Serine Hydroxymethyltransferase is a Modifier of Apc min
Author(s) -
MacFarlane Amanda J,
Perry Cheryll A,
Lin David M,
Stover Patrick J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a120-c
Subject(s) - methylation , uracil , serine hydroxymethyltransferase , dna methylation , methionine , microbiology and biotechnology , gene expression , chemistry , methyltransferase , serine , gene , biochemistry , biology , dna , amino acid , enzyme
Folate deficiency is strongly associated with increased risk for colorectal cancer (CRC). Folate deficiency impairs cellular methylation reactions and nucleotide biosynthesis, and thereby impacts chromatin structure, gene expression and genome stability. Cytoplasmic serine hydroxymethyltransferase (cSHMT) regulates folate‐mediated one‐carbon metabolism by acting as a metabolic switch. cSHMT preferentially partitions methylene tetrahydrofolate (THF) into dTMP synthesis at the expense of methionine synthesis. cSHMT also sequesters 5‐methyl THF, the substrate required for methionine synthesis. Thus, cSHMT can alter gene expression by decreasing cellular methylation capacity, and promote genome stability by decreasing rates of uracil misincorporation. Transgenic mice were generated in which cSHMT expression is diminished or eliminated. Mice with reduced cSHMT expression exhibit higher levels of uracil in DNA and increased cellular methylation capacity compared to wild type mice. Apc min /cSHMT −/+ mice developed more intestinal tumors than Apc min /cSHMT +/+ mice. Microarray analyses of colon samples demonstrates that changes in cSHMT expression affects the expression of a number of genes involved in cellular transformation. This mouse model enables the dissection of the relative contributions of uracil content in DNA and alterations in cellular methylation to colon cancer susceptibility.