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 journalArticle

286 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
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    O'Hagan, HM., Wang, W., Sen, S., DeStefano Shields, C., Lee, SS., Zhang, YW., Clements, EG., Cai, Y., Van Neste, L., Easwaran, H., Casero, RA., Sears, CL., & Baylin, SB. (2011). Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands. Cancer Cell, 20(5), 606-619. https://doi.org/10.1016/j.ccr.2011.09.012