Crystal structure of human methyl-binding domain IV glycosylase bound to abasic DNA.

Journal of Molecular Biology
Brittney A ManvillaA C Drohat

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 ...Continue Reading

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Citations

Sep 3, 2013·DNA Repair·Ángel Ramiro-MerinaTeresa Roldán-Arjona
Dec 1, 2012·Mutation Research·Ashley B SjolundJoann B Sweasy
Aug 3, 2014·Biochimica Et Biophysica Acta·Alexandra A KuznetsovaOlga S Fedorova
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May 30, 2015·DNA Repair·Alfonso Bellacosa, Alexander C Drohat
Aug 9, 2016·Chemical Reviews·Alexander C Drohat, Christopher T Coey
Sep 2, 2016·Nucleic Acids Research·Christopher T CoeyAlexander C Drohat
Apr 17, 2020·The Biochemical Journal·Hala Ouzon-ShubeitaSeongmin Lee
Apr 17, 2018·Nucleic Acids Research·Christopher T Coey, Alexander C Drohat
Dec 9, 2020·International Journal of Molecular Sciences·Fabienne HansJoanna Timmins
Dec 24, 2019·Journal of Molecular Biology·Cathia RauschM Cristina Cardoso
Jun 10, 2021·Journal of Molecular Biology·Lakshmi S PiduguAlexander C Drohat
Mar 8, 2019·Journal of the American Chemical Society·Blaine J DowAlexander C Drohat

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