title: 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.
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Schomacher
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Dandan
authors.initials: D
authors.lastname: Han
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Michael U
authors.initials: MU
authors.lastname: Musheev
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Khelifa
authors.initials: K
authors.lastname: Arab
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kienhöfer
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: von Seggern
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.|Division of Molecular Embryology, German Cancer Research Center-Zentrum für Molekulare Biologie der Universität Heidelberg (DKFZ-ZMBH) Alliance, Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D044502:Thymine DNA Glycosylase / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D049308:Dioxygenases; D044502:Thymine DNA Glycosylase; C491825:TCF21 protein, human; C473634:NEIL1 protein, human; C473642:NEIL2 protein, human