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

ABSTRACT: 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.

SUBMITTER: Zhu C

PROVIDER: S-EPMC4948311 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Zhu Chenxu C Lu Lining L Zhang Jun J Yue Zongwei Z Song Jinghui J Zong Shuai S Liu Menghao M Stovicek Olivia O Gao Yi Qin YQ Yi Chengqi C

Proceedings of the National Academy of Sciences of the United States of America 20160627 28

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 ...[more]

PMID: 27354518

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