Impact of folate deficiency on DNA stability.
Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies.
Duthie
Susan J
SJ
Rowett Research Institute, Aberdeen, United Kingdom. sd@rri.sari.ac.uk
Narayanan
Sabrina
S
Brand
Gillian M
GM
Pirie
Lynn
L
Grant
George
G
D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics; D004247:DNA / Q000235:genetics*; D005494:Folic Acid Deficiency / Q000235:genetics*; D006801:Humans; D023421:Models, Animal; D000090063:Proto-Oncogene Mas
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004247:DNA