Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands

Heather M O'Hagan, Wei Wang, Subhojit Sen, Christina DeStefano Shields, Stella S Lee, Yang W Zhang, Eriko G Clements, Yi Cai, Leander Van Neste, Hariharan Easwaran, Robert A Casero, Cynthia L Sears, Stephen B Baylin

Research output: Contribution to journalArticlepeer-review

300 Scopus citations

Abstract

Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causes relocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. Although high-expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low-expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing.

Original languageEnglish (US)
Pages (from-to)606-619
Number of pages14
JournalCancer Cell
Volume20
Issue number5
DOIs
StatePublished - Nov 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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