Abstract
The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifications are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER factor XPC-RAD23B to these lesions.
Highlights
Anil Kumar and Endogenous reactive oxygen species, free radicals and electrophiles generated by UV light, ionizing radiation and environmental pollutants, are known to induce permanentDNA damage and harmful epigenetic changes [1,2,3]
We have recently found that a five-fold rise of DNA concentrations from 0.2 nM to 1 nM induces a decrease in the nucleotide excision repair (NER)/base excision repair (BER) yield ratios from ~4.3 to ~2.7 and ~2.0 to ~1.2 in the case of Sp- and Gh-plasmids, respectively [21]
NER efficiencies in the case of linearized forms of the plasmids are correlated with the dissociation of the NER DNA lesion recognition factor XPC from the ends of the linearized plasmid that diminishes the NER efficiency
Summary
Anil Kumar and Endogenous reactive oxygen species, free radicals and electrophiles generated by UV light, ionizing radiation and environmental pollutants, are known to induce permanent. Growing evidence suggests that the BER and NER pathways can compete with one another in removing oxidatively generated lesions from double-stranded DNA [14,15,16,17]. A significant enhancement (by factor of 5–6) of the NER dual incision yields of hydantoin lesions embedded in covalently closed circular DNA plasmids (cccDNA) than in the linearized form of the same plasmid DNA (linDNA) has been observed [21,22]. The BER yields in cccDNA and linDNA did not vary by more than 20–40%, depending on the guanine lesion These surprising differences in NER and BER activities have been attributed to the lack of termini in covalently closed circular DNA, that enhance the search dynamics of the NER.
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