Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation

Cancer Cell. 2013 Oct 14;24(4):528-41. doi: 10.1016/j.ccr.2013.08.022.


Wip1 phosphatase is emerging as an important regulator of tumorigenesis, but no unifying mechanistic network has been proposed. We found that Wip1 plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences. Wip1 was required for epigenetic remodeling of repetitive DNA elements through regulation of BRCA1 interaction with HP1, the recruitment of DNA methyltransferases, and subsequent DNA methylation. Attenuation of ATM, in turn, reversed heterochromatin methylation. This mechanism was critical for the recruitment of the AID cytidine deaminase, and Wip1 levels strongly correlated with C-to-T substitutions and a total mutation load in primary breast cancers. We propose that Wip1 plays an important role in the regulation of global heterochromatin silencing and thus is critical in maintaining genome integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • BRCA1 Protein / metabolism*
  • Cell Line, Tumor
  • DNA / analysis
  • DNA Methylation*
  • Gene Silencing
  • Heterochromatin / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Mutation
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Phosphatase 2C
  • Spermatogenesis


  • BRCA1 Protein
  • Heterochromatin
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Ppm1d protein, mouse
  • Protein Phosphatase 2C

Associated data

  • GEO/GSE46103