Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome

Biochem Biophys Res Commun. 2005 Nov 25;337(3):875-80. doi: 10.1016/j.bbrc.2005.09.122. Epub 2005 Sep 29.

Abstract

ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Aminopurine / pharmacology
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • DNA Damage / drug effects
  • DNA Damage / physiology*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / physiology*
  • Fibroblasts / radiation effects
  • Gamma Rays
  • Gene Expression Regulation / genetics
  • Gene Silencing / drug effects
  • Gene Silencing / physiology*
  • Gene Silencing / radiation effects
  • Heterochromatin / metabolism
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • X Chromosome / drug effects
  • X Chromosome / genetics*
  • X Chromosome / radiation effects
  • X Chromosome Inactivation / drug effects
  • X Chromosome Inactivation / physiology*
  • X Chromosome Inactivation / radiation effects

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Heterochromatin
  • Tumor Suppressor Proteins
  • 2-Aminopurine
  • Atr protein, mouse
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases