Folate, DNA stability and colo-rectal neoplasia.
Lower levels of dietary folate are associated with the development of epithelial cell tumours in man, particularly colo-rectal cancer. In the majority of epidemiological studies blood folate or reported folate intake have been shown to be inversely related to colo-rectal cancer risk. Folate, via its pivotal role in C1 metabolism, is crucial both for DNA synthesis and repair, and for DNA methylation. This function is compromised when vitamin B12 is low. Vitamin B12 deficiency has been shown to increase biomarkers of DNA damage in man but there is no evidence directly linking low vitamin B12 with cancer. Disturbingly, folate and vitamin B12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How folate and/or vitamin B12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instability in the DNA molecule via a futile cycle of uracil misincorporation and removal. The relative importance of these two pathways may become clear by determining both DNA stability and cytosine methylation in individuals with different polymorphic variants of key folate-metabolising enzymes. 5,10-Methylenetetrahydrofolate reductase converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and thereby controls whether folate is employed for DNA synthesis or DNA methylation. Colo-rectal cancer risk is decreased in subjects homozygous for a common variant (C677T) of the gene coding for this enzyme, suggesting that DNA synthesis and repair may be 'enhanced' in these individuals. Evidence from animal and human studies is presented here in support of folate acting to maintain genomic stability through both these mechanisms.
Duthie
Susan J
SJ
Division of Cellular Integrity, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK. sd@rri.sari.ac.uk
Narayanan
Sabrina
S
Sharp
Linda
L
Little
Julian
J
Basten
Graham
G
Powers
Hilary
H
D019731:Carbon-Nitrogen Ligases / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation; D004260:DNA Repair; D005492:Folic Acid / Q000008:administration & dosage*; D005494:Folic Acid Deficiency / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D012307:Risk Factors; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000378:metabolism; D014806:Vitamin B 12 Deficiency / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D005492:Folic Acid; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase; D014805:Vitamin B 12