ArticleProceedings of the National Academy of Sciences of the United States of America2018
Uncovering universal rules governing the selectivity of the archetypal DNA glycosylase TDG.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Structural basis of DNA replication fidelity of the Mpox virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural underpinnings of mutation rate variations in the human genome.Nucleic acids research · 2023Article
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- Kinetic Analysis of the Effect ofBiochemistry · 2022Article
- Kinetics and thermodynamics of BI-BII interconversion altered by T:G mismatches in DNA.Biophysical journal · 2022Article
- The base excision repair process: comparison between higher and lower eukaryotes.Cellular and molecular life sciences : CMLS · 2021Review
- Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition.Nucleic acids research · 2021Article
- Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path.Nature communications · 2020Article
- Impact of 5-formylcytosine on the melting kinetics of DNA by 1H NMR chemical exchange.Nucleic acids research · 2020Article
- HMGB1 Recruits TET2/AID/TDG to Induce DNA Demethylation in STAT3 Promoter in CD4Journal of immunology research · 2020Article
- Effect of the thymine-DNA glycosylase rs4135050 variant on Saudi smoker population.Molecular genetics & genomic medicine · 2019Article
- Nucleosomes and the three glycosylases: High, medium, and low levels of excision by the uracil DNA glycosylase superfamily.DNA repair · 2018Article
- Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Thymine DNA glycosylase (TDG) is a pivotal enzyme with dual roles in both genome maintenance and epigenetic regulation. TDG is involved in cytosine demethylation at CpG sites in DNA. Here we have used molecular modeling to delineate the lesion search and DNA base interrogation mechanisms of TDG. First, we examined the capacity of TDG to interrogate not only DNA substrates with 5-carboxyl cytosine modifications but also G:T mismatches and nonmismatched (A:T) base pairs using classical and accelerated molecular dynamics. To determine the kinetics, we constructed Markov state models. Base interrogation was found to be highly stochastic and proceeded through insertion of an arginine-containing loop into the DNA minor groove to transiently disrupt Watson-Crick pairing. Next, we employed chain-of-replicas path-sampling methodologies to compute minimum free energy paths for TDG base extrusion. We identified the key intermediates imparting selectivity and determined effective free energy profiles for the lesion search and base extrusion into the TDG active site. Our results show that DNA sculpting, dynamic glycosylase interactions, and stabilizing contacts collectively provide a powerful mechanism for the detection and discrimination of modified bases and epigenetic marks in DNA.
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