Add time:07/24/2019         Source:sciencedirect.com

Glycidaldehyde (GDA) is a bifunctional alkylating agent that has been shown to be mutagenic in vitro and carcinogenic in rodents. However, the molecular mechanism by which it exerts these effects is not established. GDA is capable of forming exocyclic hydroxymethyl-substituted etheno adducts on base residues in vitro. One of them, 7-(hydroxymethyl)-1,N6-ethenoadenine (7-hm-ɛA), was identified as the principal adduct in mouse skin treated with GDA or a glycidyl ether. In this work, using defined oligonucleotides containing a site-specific 7-hm-ɛA, the human and mouse alkylpurine-DNA-N-glycosylases (APNGs), responsible for the removal of the analogous 1,N6-ethenoadenine (ɛA) adduct, are shown to recognize and excise 7-hm-ɛA. Such an activity can be significantly modulated by both 5′ neighboring and opposite sequence contexts. The efficiency of human or mouse APNG for excision of 7-hm-ɛA is about half that, or similar to the excision of ɛA, respectively. When human or mouse cell-free extracts were tested, however, the extent of 7-hm-ɛA excision is dramatically lower than that for ɛA, suggesting that, in the crude extracts, the APNG activities toward these two adducts are differentially affected. Using cell-free extracts from APNG deficient mice, this enzyme is shown to be the primary glycosylase excising 7-hm-ɛA. A structural approach, using molecular modeling, was employed to examine how the structure of the 7-hm-ɛA adduct affects DNA conformation, as compared to the ɛA adduct. These novel substrate specificities could have both biological and structural implications.

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