Uracil in DNA: error or signal?

Uracil  in DNA: error or signal?

Speaker: Beata G. Vertessy

Affiliation: Howard Hughes Scholar, Sci. Advisor
Institute of Enzymology
Hungarian Academy of Sciences

Host: Maria Arménia Carrondo

Abstract:

Uracil, a close thymine analog, is traditionally considered as a mistake  in DNA.
Repair of uracil as a cytosine deamination product is essential, but the repair enzyme uracil-DNA glycosylase usually also eliminates thymine-replacing, "innocent" uracils, as well. Inhibition of dUTPase and/or thymidylate synthase results in elevated celluar dUTP/dTTP ratios that, due to the suboptimal specificity of DNA polymerases, leads to incorporation of thymine-replacing uracils to such an extent that overloads the repair apparatus and induces apoptosis (thymine-less cell death). This research field is of interest for therapeutical applications (antimicrobial and anti-tumor strategies). New insights into structure and function of the dUTPase enzyme family will be presented. Recent experimental data also argue for a re-interpretation of the traditional view on uracil being solely a mistake in DNA. Actually, uracil-DNA may be at least transiently tolerated in different organisms, and it may possess physiological or developmental role. Due to lack of dUTPase and uracil-DNA glycosylase in the fruit fly larvae, uracil-DNA is suggested to be a developmental death signal in Drosophila. Elevated uracil content in DNA in the larvae and the existence of a uracil-DNA degrading nuclease under strict developmental control present key pieces of experimental evidence
in this hypothesis.