Misincorporation of uracil into DNA as possible contributor to neuronal aging and abiotrophy

Abstract

Neuronal aging and abiotrophy may be related to the abnormal presence of uracil in DNA. Evidence which could support this hypothesis exists: 1) DNA polymerase beta, the only nuclear DNA polymerase present in adult neurons which is able to repair damaged DNA, incorporates dUTP or dTTP with the same efficiency. This suggests that in adult neurons the incorporation of dUTP into DNA is solely dependent on the relative intracellular concentration of dUTP; 2) uracil into DNA also arises from cytosine deamination; 3) at birth, when neurons stop proliferating, uracil DNA-glycosylase, the enzyme responsible of the removal of uracil from DNA, nearly disappears; 4) a significant replacement of thymine by uracil in DNA could produce genetic instability which in turn could affect the recognition of DNA sequences by enzymes and/or by regulatory DNA binding proteins. Thus enzymatic defects which might alter the intracellular dUTP pool, in different neuronal systems, could account for the multiplicity of the clinical manifestations of aging and neurodegenerative disorders. The increase of the age-specific rate of abiotrophic diseases may be due to accumulation with time of uracil containing DNA.