Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair

NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-07, Vol.113 (28), p.7792-7797
Main Authors: Zhu, Chenxu, Lu, Lining, Zhang, Jun, Yue, Zongwei, Song, Jinghui, Zong, Shuai, Liu, Menghao, Stovicek, Olivia, Gao, Yi Qin, Yi, Chengqi
Format: Article
Language:English
Subjects:
Biological Sciences
Catalysis
Computer Simulation
Crystal structure
Crystallography
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA Glycosylases - metabolism
DNA Repair
Enzymes
Escherichia coli
Furans
Humans
Models, Chemical
Substrates
Thymine - analogs & derivatives
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Summary:NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)—a preferred substrate—for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzyme-promoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1604591113