TY - JOUR

T1 - A non-canonical nucleotide from viral genomes interferes with the oxidative DNA damage repair system

AU - Yudkina, Anna V

AU - Endutkin, Anton V

AU - Diatlova, Evgeniia A

AU - Zharkov, Dmitry O

N1 - This research was supported by the Russian Science Foundation (grant 21-64-00017, DNA glycosylase experiments) and the Russian Ministry of Science and Higher Education (project 075-15-2022-263, DNA polymerase experiments). Partial salary support from the Russian Ministry of Science and Higher Education (project FSUS-2020-0035) is acknowledged. Copyright © 2023 Elsevier B.V. All rights reserved.

PY - 2024/1

Y1 - 2024/1

N2 - Oxidative 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 lower activity on Z:8-oxoG mispairs. Similar preferences were observed for Fpg and MutY from different bacterial species (Escherichia coli, Staphylococcus aureus and Lactococcus lactis). Overall, the relaxed control of 8-oxoG in the presence of the Z nucleotide may be a source of additional mutagenesis in the genomes of bacteriophages or bacteria that have survived the viral invasion.

AB - Oxidative 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 lower activity on Z:8-oxoG mispairs. Similar preferences were observed for Fpg and MutY from different bacterial species (Escherichia coli, Staphylococcus aureus and Lactococcus lactis). Overall, the relaxed control of 8-oxoG in the presence of the Z nucleotide may be a source of additional mutagenesis in the genomes of bacteriophages or bacteria that have survived the viral invasion.

KW - 2,6-diaminopurine

KW - 8-oxoguanine

KW - DNA damage

KW - DNA glycosylases

KW - DNA polymerases

KW - DNA repair

KW - Non-canonical genomes

KW - Genome, Viral

KW - Oxidative Stress

KW - Humans

KW - Nucleotides/metabolism

KW - Escherichia coli/metabolism

KW - DNA Repair

KW - DNA Glycosylases/metabolism

KW - DNA Damage

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85178554216&origin=inward&txGid=6d4fbd10fa7a4f4d732aa59e480963f8

UR - https://www.mendeley.com/catalogue/6683736d-bc66-3616-a92c-4f21cadefc3a/

U2 - 10.1016/j.dnarep.2023.103605

DO - 10.1016/j.dnarep.2023.103605

M3 - Article

C2 - 38042029

VL - 133

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

M1 - 103605

ER -