Robust excision of different purine lesions by homologs thymine DNA glycosylase and mismatch-specific uracil DNA-glycosylase.

Authors

Kurt B Espinosa, Xiao Ding, Hardler W Servius, Lakshmi S Pidugu, Jeehiun K Lee, Alexander C Drohat

Published in

The Journal of biological chemistry. Pages 113446. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

DNA bases are subject to alkylation, deamination, and oxidation, yielding mutagenic and cytotoxic lesions implicated in cancer and neurodegenerative disease. The damage is countered by DNA glycosylases, which hydrolyze the N-glycosyl bond to release the lesion and initiate base excision repair. One glycosylase family is represented by human TDG (thymine DNA glycosylase) and Escherichia coli MUG (mismatch-specific uracil DNA-glycosylase), which exhibit 32% sequence identity. TDG excises thymine/uracil from guanine mispairs, 5-formylcytosine, 5-carboxylcytosine, and 3,N⁴-ethenocytosine (εC), while MUG excises εC and mismatched uracil. Remarkably, TDG was shown to excise a purine lesion, 7,8-dihydro-8-oxoadenine (8OA), much faster than pyrimidine substrates, while MUG lacks 8OA activity. To define the purine specificity of these enzymes we performed structure-activity relationship studies, determining the rate constant for excision of 10 different purines from DNA. We also performed theoretical calculations to determine chemical properties of the purines that could influence their enzymatic excision, including N9 acidity, an indicator of leaving group ability during bond cleavage, tautomer stability, and electrostatic potential maps. TDG activity is 4-7 orders of magnitude higher for 8OA versus other purines, while MUG exhibits strikingly high activity and specificity for excision of xanthine. Rate enhancements for TDG excision of 8OA (10^9.2), other purines (≤10^4.5), uracil (10^8.2), and thymine (10^7.1) reveal high specificity for 8OA, and those of MUG for excising xanthine (10^7.8), other purines (≤10^5.2), and uracil (10^7.8), indicate high xanthine specificity. The results suggest mechanisms for purine specificity and provide evidence that 8OA and xanthine are biological substrates of TDG and MUG, respectively.

PMID:
42595112
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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