Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage

Abstract

Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent incorporation of uracil into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks. Both high DNA uracil levels and elevated micronucleus frequency (a measure of chromosome breaks) are reversed by folate administration. A significant proportion of the U.S. population has low folate levels, in the range associated with elevated uracil misincorporation and chromosome breaks. Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.

Figures

Figure 1

Uracil levels in DNA and micronuclei frequencies were elevated in folate-deficient subjects and were reduced by folate supplementation. Uracil and micronuclei values were determined in 25 human subjects as described (31, 37). Open and solid symbols represent levels before and after supplementation with 5 mg per day folic acid, respectively. Squares represent individuals with deficient erythrocyte folate levels but borderline plasma folate levels (6 ng/ml ≥ plasma folate ≥4 ng/ml). Triangles are averaged values before and after supplementation of an individual with Crohn disease (19). (A) Uracil levels before and after folate supplementation (5 mg per day). (B and C) Micronuclei values in reticulocytes (B) and erythrocytes (C) before and after folate supplementation.

Figure 2

Uracil levels and micronuclei values were elevated in a subject with Crohn disease and reduced by supplementation of folinic and folic acid. Uracil was measured (31) in DNA isolated from frozen blood samples (19). Uracil levels: ⋄, before supplementation; ♦, after supplementation. Micronucleus frequency (19): ○, before supplementation; •, after supplementation.