Uracil in DNA--its biological significance

Abstract

Uracil may arise in DNA as a result of spontaneous cytosine deamination and/or misincorporation of dUMP during DNA replication. In this paper we will review: (i) sources of the origin of uracil in DNA; (ii) some properties of the enzymes responsible for the excision of uracil and their role in the Ig diversification process, which comprises somatic hypermutation and class switch recombination; and (iii) consequences of cytosine deamination in other than the Ig loci, in cell types different than B lymphocytes. Furthermore, the issue concerning the basal level of uracil in DNA and consequences of the presence of U:A pairs for DNA stability and cell functions will be discussed. Finally, we will discuss the clinical significance of aberrant uracil incorporation into DNA and possible involvement of aberrantly expressed AID and the enzyme-induced presence of uracil, in carcinogenesis. Based on the literature data we conclude/hypothesize that the non-canonical base uracil may be present and well tolerated in DNA mostly as U:A pairs, likely in quantities of 10(4) per genome. Although a role of uracil in DNA is not fully defined, it is possible that an ancestral system which once used uracil in primordial genetic material (uracil-DNA), may have evolved to use this molecule in regulatory processes such as: (i) meiotic cell division to facilitate chromatid exchange during crossing-over (in spermatocytes); (ii) it is possible that uracil present in DNA may be a signaling molecule during metamorphosis of Drosophila melanogaster; and (iii) during transcription since some regulatory proteins (Escherichia coli lac repressor) and GCN4 can recognize uracil versus thymine in specific DNA regulatory sequences. Moreover, recent data suggest that in transcriptionally active chromatin the dUTP/dTTP pool may be significantly increased, which in turn may lead to massive uracil incorporation into DNA.