Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation

Nat Struct Mol Biol. 2016 Feb;23(2):116-124. doi: 10.1038/nsmb.3151. Epub 2016 Jan 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Line, Tumor
  • DNA Glycosylases / chemistry
  • DNA Glycosylases / metabolism*
  • DNA Methylation*
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / chemistry
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
  • Dioxygenases / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Thymine DNA Glycosylase / metabolism*
  • Xenopus / embryology
  • Xenopus / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • TCF21 protein, human
  • Dioxygenases
  • DNA Glycosylases
  • NEIL1 protein, human
  • Thymine DNA Glycosylase
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • NEIL2 protein, human