title: Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome.
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.
authors.affiliation: Department of Human Genetics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Salstrom
authors.forename: Silvia
authors.initials: S
authors.lastname: Diaz-Perez
authors.forename: Shareef
authors.initials: S
authors.lastname: Nahas
authors.forename: Youko
authors.initials: Y
authors.lastname: Matsuno
authors.forename: David
authors.initials: D
authors.lastname: Dawson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.forename: York
authors.initials: Y
authors.lastname: Marahrens
mesh_terms: D015075:2-Aminopurine / Q000494:pharmacology; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006570:Heterochromatin / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014960:X Chromosome / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D049951:X Chromosome Inactivation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D025521:Tumor Suppressor Proteins; D015075:2-Aminopurine; C576897:Atr protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases