Abstract
Human telomeres as well as more than 40% of human genes near the promoter regions have been found to contain the sequence that may form a G-quadruplex structure. Other non-canonical DNA structures comprising bulges, hairpins, or bubbles may have a functionally important role during transcription, replication, or recombination. The guanine-rich regions of DNA are hotspots of oxidation that forms 7,8-dihydro-8-oxoguanine, thymine glycol, and abasic sites: the lesions that are handled by the base excision repair pathway. Nonetheless, the features of DNA repair processes in non-canonical DNA structures are still poorly understood. Therefore, in this work, a comparative analysis of the efficiency of the removal of a damaged nucleotide from various G-quadruplexes and bulged structures was performed using endonuclease VIII-like 1 (NEIL1), human 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III (NTH1), and prokaryotic formamidopyrimidine-DNA glycosylase (Fpg), and endonuclease VIII (Nei). All the tested enzymes were able to cleave damage-containing bulged DNA structures, indicating their important role in the repair process when single-stranded DNA and intermediate non–B-form structures such as bubbles and bulges are formed. Nevertheless, our results suggest that the ability to cleave damaged quadruplexes is an intrinsic feature of members of the H2tH structural family, suggesting that these enzymes can participate in the modulation of processes controlled by the formation of quadruplex structures in genomic DNA.
Highlights
Exogenous and endogenous agents such as very reactive cell metabolites, external environmental compounds, and ionizing or UV irradiation constantly damage cellular DNA
We analyzed the ODNs under study by Circular dichroism (CD) spectroscopy, under several buffering conditions
DNA glycosylases of different structural families form completely different contacts in the substrate-binding site and in the active pocket, and different amino acid residues participate in specific recognition of the damaged nucleotide and in catalysis
Summary
Exogenous and endogenous agents such as very reactive cell metabolites, external environmental compounds, and ionizing or UV irradiation constantly damage cellular DNA. The main sources of endogenous damage to DNA are reactive oxygen species (ROS). The latter give rise to various DNA base lesions, including thymine glycol (Tg), 7,8-dihydro-8-oxoguanine (8-oxoguanine, oxoG), 4,6diamino-5-formamidopyrimidine (Fapy-A), and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G; Wallace, 2002; Evans et al, 2004). Activity of DNA Glycosylases on Non–B-Form DNA instability (Wallace, 2002) The bulk of this endogenous burden is managed by base excision DNA repair (BER). The latter involves a few DNA N-glycosylases specific to the removal of a large spectrum of alkylated, oxidized, or deaminated bases, and sometimes normal mispaired bases; this process generates abasic (apurinic/apyrimidinic; AP) sites in DNA (Friedman and Stivers, 2010; Svilar et al, 2011)
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