Thymine DNA glycosylase exhibits negligible affinity for nucleobases that it removes from DNA

Malik, Shuja S.; Coey, Christopher T.; Varney, Kristen M.; Pozharski, Edwin; Drohat, Alexander C.

doi:10.1093/nar/gkv890

Thymine DNA glycosylase exhibits negligible affinity for nucleobases that it removes from DNA

Journal Article · Thu Sep 10 00:00:00 EDT 2015 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkv890· OSTI ID:1625547

Malik, Shuja S. ^[1]; Coey, Christopher T. ^[2]; Varney, Kristen M. ^[3]; Pozharski, Edwin ^[4]; Drohat, Alexander C. ^[3]

Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Dept. of Biochemistry and Molecular Biology; DOE/OSTI
Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Dept. of Biochemistry and Molecular Biology
Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Dept. of Biochemistry and Molecular Biology; Univ. of Maryland, Baltimore, MD (United States). Marlene and Stewart Greenebaum Cancer Center
Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Dept. of Biochemistry and Molecular Biology; Univ. of Maryland, Baltimore, MD (United States). Marlene and Stewart Greenebaum Cancer Center; Inst. for Bioscience and Biotechnology Research, Rockville, MD (United States). Center for Biomolecular Therapeutics

Thymine DNA Glycosylase (TDG) performs essential functions in maintaining genetic integrity and epigenetic regulation. Initiating base excision repair, TDG removes thymine from mutagenic G·T mispairs caused by 5-methylcytosine (mC) deamination and other lesions including uracil (U) and 5-hydroxymethyluracil (hmU). In DNA demethylation, TDG excises 5-formylcytosine (fC) and 5- carboxylcytosine (caC), which are generated from mC by Tet (ten–eleven translocation) enzymes. Using improved crystallization conditions, we solved high resolution (up to 1.45 A) structures of TDG enzyme– ' product complexes generated from substrates including G·U, G·T, G·hmU, G·fC and G·caC. The structures reveal many new features, including key water mediated enzyme–substrate interactions. Together with nuclear magnetic resonance experiments, the structures demonstrate that TDG releases the excised base from its tight product complex with abasic DNA, contrary to previous reports. Moreover, DNAfree TDG exhibits no significant binding to free nucleobases (U, T, hmU), indicating a Kd >> 10 mM. The structures reveal a solvent-filled channel to the active site, which might facilitate dissociation of the excised base and enable caC excision, which involves solvent-mediated acid catalysis. Dissociation of the excised base allows TDG to bind the beta rather than the alpha anomer of the abasic sugar, which might stabilize the enzyme–product complex.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1625547

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 19 Vol. 43; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Dynamics of the excised base release in thymine DNA glycosylase during DNA repair process Da, Lin-Tai; Shi, Yi; Ning, Guodong Nucleic Acids Research, Vol. 46, Issue 2 https://doi.org/10.1093/nar/gkx1261	journal	December 2017
Defining the impact of sumoylation on substrate binding and catalysis by thymine DNA glycosylase Coey, Christopher T.; Drohat, Alexander C. Nucleic Acids Research, Vol. 46, Issue 10 https://doi.org/10.1093/nar/gky278	journal	April 2018
Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process Da, Lin-Tai; Yu, Jin Nucleic Acids Research, Vol. 46, Issue 11 https://doi.org/10.1093/nar/gky386	journal	May 2018
Sulfolobus acidocaldarius UDG Can Remove dU from the RNA Backbone: Insight into the Specific Recognition of Uracil Linked with Deoxyribose Yi, Gang-Shun; Wang, Wei-Wei; Cao, Wei-Guo Genes, Vol. 8, Issue 1 https://doi.org/10.3390/genes8010038	journal	January 2017
TET-mediated active DNA demethylation: mechanism, function and beyond Wu, Xiaoji; Zhang, Yi Nature Reviews Genetics, Vol. 18, Issue 9 https://doi.org/10.1038/nrg.2017.33	journal	May 2017

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Thymine DNA glycosylase exhibits negligible affinity for nucleobases that it removes from DNA

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