On the nature of folic-acid-sensitive fragile sites in human chromosomes: an hypothesis.

The methyl groups of thymine and 5-methylcytosine exposed along the major groove of the DNA double helix are involved in the binding of specific proteins to specific DNA regions. It is hypothesized that folate-sensitive fragile sites on chromosomes appear as a result of heritable defects of DNA methylation along a region normally binding a folding protein involved in chromosome condensation. Impairment of DNA-folding-protein interaction would result. A superimposed folate deficiency, or any condition leading to impaired thymidylate biosynthesis, would promote misincorporation into DNA of uracil in place of thymine, thus producing a further loss of methyl groups at the fragile site and eventually precluding a full DNA-folding-protein interaction. A localized collapse of the chromosome structure would follow.