A non-canonical nucleotide from viral genomes interferes with the oxidative DNA damage repair system

DNA Repair (Amst). 2023 Nov 20;133:103605. doi: 10.1016/j.dnarep.2023.103605. Online ahead of print.ABSTRACTOxidative damage is a major source of genomic instability in all organisms with the aerobic metabolism. 8-Oxoguanine (8-oxoG), an abundant oxidized purine, is mutagenic and must be controlled by a dedicated DNA repair system (GO system) that prevents G:C→T:A transversions through an easily formed 8-oxoG:A mispair. In some forms, the GO system is present in nearly all cellular organisms. However, recent studies uncovered many instances of viruses possessing non-canonical nucleotides in their genomes. The features of genome damage and maintenance in such cases of alternative genetic chemistry remain barely explored. In particular, 2,6-diaminopurine (Z nucleotide) completely substitutes for A in the genomes of some bacteriophages, which have evolved pathways for dZTP synthesis and specialized polymerases that prefer dZTP over dATP. Here we address the ability of the GO system enzymes to cope with oxidative DNA damage in the presence of Z in DNA. DNA polymerases of two different structural families (Klenow fragment and RB69 polymerase) were able to incorporate dZMP opposite to 8-oxoG in the template, as well as 8-oxodGMP opposite to Z in the template. Fpg, a 8-oxoguanine-DNA glycosylase that discriminates against 8-oxoG:A mispairs, also did not remove 8-oxoG from 8-oxoG:Z mispairs. However, MutY, a DNA glycosylase that excises A from pairs with 8-oxoG, had a significantly...
Source: DNA Repair - Category: Genetics & Stem Cells Authors: Source Type: research