[Oxidation and deamination of nucleobases as an epigenetic tool]. / Oksydacyjnie modyfikowane i deaminowane zasady DNA jako czynnik epigenetyczny.

 Recent discoveries have demonstrated that 5-methylcytosine (5mC) may be hydroxymethylated to 5-hydroxymethylcytosine (5hmC) in mammals and that genomic DNA may contain about 0.02-0.7% of 5hmC. The aforementioned modification is the key intermediate of active DNA demethylation and has been named "the sixth base in DNA". Although active DNA demethylation in mammals is still controversial, the most plausible mechanism/s of active 5mC demethylation include involvement of three families of enzymes; i) Tet, which is involved in hydroxylation of 5mC to form 5hmC, which can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC); ii) deamination of 5mC (or 5hmC) by AID/APOBEC to form thymine or 5-hydroxymethyluracil (5hmU) mispaired with guanine; iii) the BER pathway induced by involvement of TDG glycosylase to replace the above described base modification (5fC, 5caC, 5hmU) with cytosine to demethylate DNA. A plausible scenario for engagement of TDG glycosylase (or some other G-T glycosylase) is through prior deamination of 5-mC to thymine, which generates a G: T substrate for the enzyme. Here cytidine deaminase of the AID/APOBEC family was implicated in the deamination step. It is possible that TDG may act in concert with these deaminases. It seems that mutations are not the only effect of oxidatively modified DNA bases. These, as yet, understudied aspects of the damage suggest a potential for 8-oxoguanine (8-oxoGua) to affect gene expression via chromatin relaxation. It is possible that 8-oxoGua presence in specific DNA sequences may be widely used for transcription regulation, which suggests the epigenetic nature of 8-oxoGua presence in DNA.

Uracil in DNA--its biological significance.

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.

[Uracil in DNA--friend or foe?]. / Uracyl w DNA--przyjaciel czy wróg?

Uracil may arise in DNA, in small quantities as a result of spontaneous cytosine deamination or/and misincorporation of dUMP during DNA replication. However, just recently uracil formation via enzymatic deamiantion of cytosine, has been found to underlies diversification of Ig genes and inhibition of retroviral infection. DNA deamination is the only known programme in mammalian development in which the coding capacity of the genome is changed by targeted modification of deoxycitidine. In this paper we will review: i/sources of the origin of uracil in DNA, ii/the function of activation induced cytidine deaminase (AID) the enzyme which is responsible for cytidine deamination in Ig genes of B cell clones iii/some properties of the enzymes responsible for the excision of uracil. The role of uracil and above mentioned enzymes in Ig diversification process, which comprises somatic hypermutation and class switch recombination will also be discussed. Finally, we will discuss possible involvement of aberrantly expressed AID and presence of uracil in DNA, in carcinogenesis.