Abstract
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. Apcmin/cSHMT−/+ mice developed more intestinal tumors than Apcmin/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.
Published Version
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