DNA Glycosylases hydrolytically excise damaged or mismatched bases from DNA. hTDG (human thymidine DNA glycosylase), is active against G·T mispairs and other lesions. We have shown that 5‐fluorouracil (FU), as well as its 5‐chlorouracil (ClU) and 5‐bromouracil (BrU) are excised much faster than the traditional G·T substrate (Bennett, M.T., et al JACS 128, –12519). Previous studies indicate that hTDG is specific for lesions paired with G and located at CpG sites. We investigated the contribution of the 5′‐base pair to hTDG activity using single turnover kinetics with substrates containing FU, ClU, and BrU lesions. For ClU, kmax was 10‐fold lower for GpG·ClU, 5‐fold lower for TpG·ClU, and 85‐fold lower for ApG·ClU as compared to CpG·ClU. Similar trends were observed for FU and BrU. Our findings indicate that hTDG is more active against FU·G, ClU·G, and BrU·G lesions in any DNA context than against CpG·T lesions. Thus, hTDG may offer general protection against ClU·G and BrU·G lesions, which may arise in DNA at sites of inflammation. However, the much slower activity for FU·A, ClU·A, and BrU·A pairs suggests a limited protective role for hTDG against these lesions.
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