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Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation.

ABSTRACT: DNA 5-methylcytosine is a dynamic epigenetic mark with important roles in development and disease. In the Tet-Tdg demethylation pathway, methylated cytosine is iteratively oxidized by Tet dioxygenases, and unmodified cytosine is restored via thymine DNA glycosylase (Tdg). Here we show that human NEIL1 and NEIL2 DNA glycosylases coordinate abasic-site processing during TET-TDG DNA demethylation. NEIL1 and NEIL2 cooperate with TDG during base excision: TDG occupies the abasic site and is displaced by NEILs, which further process the baseless sugar, thereby stimulating TDG-substrate turnover. In early Xenopus embryos, Neil2 cooperates with Tdg in removing oxidized methylcytosines and specifying neural-crest development together with Tet3. Thus, Neils function as AP lyases in the coordinated AP-site handover during oxidative DNA demethylation.

SUBMITTER: Schomacher L

PROVIDER: S-EPMC4894546 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation.

Schomacher Lars L Han Dandan D Musheev Michael U MU Arab Khelifa K Kienhöfer Sabine S von Seggern Annika A Niehrs Christof C

Nature structural & molecular biology 20160111 2

DNA 5-methylcytosine is a dynamic epigenetic mark with important roles in development and disease. In the Tet-Tdg demethylation pathway, methylated cytosine is iteratively oxidized by Tet dioxygenases, and unmodified cytosine is restored via thymine DNA glycosylase (Tdg). Here we show that human NEIL1 and NEIL2 DNA glycosylases coordinate abasic-site processing during TET-TDG DNA demethylation. NEIL1 and NEIL2 cooperate with TDG during base excision: TDG occupies the abasic site and is displaced ...[more]

PMID: 26751644

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