Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome.
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.
Ouyang
Yan
Y
Department of Human Genetics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Salstrom
Jennifer
J
Diaz-Perez
Silvia
S
Nahas
Shareef
S
Matsuno
Youko
Y
Dawson
David
D
Teitell
Michael A
MA
Horvath
Steve
S
Riggs
Arthur D
AD
Gatti
Richard A
RA
Marahrens
York
Y
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
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