ArticleJournal of molecular biology2012
Crystal structure of human methyl-binding domain IV glycosylase bound to abasic DNA.
Article in Journal of molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Mapping DNA glycosylase binding across lesion sequence contexts reveals extended sequence and structural recognition logic.Nature communications · 2026Article
- Repair and DNA Polymerase Bypass of Clickable Pyrimidine Nucleotides.Biomolecules · 2024Article
- Backbone Conformational Equilibrium in Mismatched DNA Correlates with Enzyme Activity.Biochemistry · 2023Article
- Divergent structures of Mammalian and gammaherpesvirus uracil DNA glycosylases confer distinct DNA binding and substrate activity.DNA repair · 2023Article
- Structural Insights into the Mechanism of Base Excision by MBD4.Journal of molecular biology · 2021Article
- Focus on DNA Glycosylases-A Set of Tightly Regulated Enzymes with a High Potential as Anticancer Drug Targets.International journal of molecular sciences · 2020Review
- Catalytic mechanism of the mismatch-specific DNA glycosylase methyl-CpG-binding domain 4.The Biochemical journal · 2020Article
- Defining the Role of Nucleotide Flipping in Enzyme Specificity UsingJournal of the American Chemical Society · 2019Article
- Defining the impact of sumoylation on substrate binding and catalysis by thymine DNA glycosylase.Nucleic acids research · 2018Article
- Readers of DNA methylation, the MBD family as potential therapeutic targets.Pharmacology & therapeutics · 2018Review
- Structural basis of damage recognition by thymine DNA glycosylase: Key roles for N-terminal residues.Nucleic acids research · 2016Article
- Role of Base Excision "Repair" Enzymes in Erasing Epigenetic Marks from DNA.Chemical reviews · 2016Review
- Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites.DNA repair · 2015Review
- Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.Scientific reports · 2014Article
- 5-methylcytosine recognition by Arabidopsis thaliana DNA glycosylases DEMETER and DML3.Biochemistry · 2014Article
- Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.Nucleic acids research · 2014Article
- Structural basis of the versatile DNA recognition ability of the methyl-CpG binding domain of methyl-CpG binding domain protein 4.The Journal of biological chemistry · 2013Article
- Structural characterization of a mouse ortholog of human NEIL3 with a marked preference for single-stranded DNA.Structure (London, England : 1993) · 2013Article
- Recent advances in the structural mechanisms of DNA glycosylases.Biochimica et biophysica acta · 2013Review
- Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA.Nucleic acids research · 2012Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The mammalian repair protein MBD4 (methyl-CpG-binding domain IV) excises thymine from mutagenic G·T mispairs generated by deamination of 5-methylcytosine (mC), and downstream base excision repair proteins restore a G·C pair. MBD4 is also implicated in active DNA demethylation by initiating base excision repair of G·T mispairs generated by a deaminase enzyme. The question of how mismatch glycosylases attain specificity for excising thymine from G·T, but not A·T, pairs remains largely unresolved. Here, we report a crystal structure of the glycosylase domain of human MBD4 (residues 427-580) bound to DNA containing an abasic nucleotide paired with guanine, providing a glimpse of the enzyme-product complex. The mismatched guanine remains intrahelical, nestled into a recognition pocket. MBD4 provides selective interactions with the mismatched guanine (N1H, N2H(2)) that are not compatible with adenine, which likely confer mismatch specificity. The structure reveals no interactions that would be expected to provide the MBD4 glycosylase domain with specificity for acting at CpG sites. Accordingly, we find modest 1.5- to 2.7-fold reductions in G·T activity upon altering the CpG context. In contrast, 37- to 580-fold effects were observed previously for thymine DNA glycosylase. These findings suggest that specificity of MBD4 for acting at CpG sites depends largely on its methyl-CpG-binding domain, which binds preferably to G·T mispairs in a methylated CpG site. MBD4 glycosylase cannot excise 5-formylcytosine (fC) or 5-carboxylcytosine (caC), intermediates in a Tet (ten eleven translocation)-initiated DNA demethylation pathway. Our structure suggests that MBD4 does not provide the electrostatic interactions needed to excise these oxidized forms of mC.
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