Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange.
Cells derived from ataxia telangiectasia (A-T) patients exhibit defective cell cycle checkpoints because of mutations in the gene encoding ATM (ataxia telangiectasia mutated). After exposure to ionizing radiation (IR), A-T cells exhibit sensitivity to IR-induced cellular damage that results in increased chromosome aberrations and cell death (radiosensitivity). ATM is a member of a family of kinases that become activated in response to DNA damage. We showed that even transient inhibition of ATM kinase for 1 hour, initiated 15 minutes after cellular irradiation, resulted in an accumulation of persistent chromosome aberrations and increased cell death. Using reversible inhibitors of DNA-PK (DNA-dependent protein kinase), another kinase involved in responding to DNA damage, and ATM, we showed that these two kinases acted through distinct DNA repair mechanisms: ATM resolved DNA damage through a mechanism involving sister chromatid exchange (SCE), whereas DNA-PK acted through nonhomologous end joining. Furthermore, because DNA damage-induced SCE occurred in A-T fibroblasts that lack functional ATM protein, and the inhibitors of ATM kinase had no effect on DNA damage-induced SCE in A-T fibroblasts, we showed that the consequences of short-term inhibition of the kinase activity of ATM and adaptation to ATM protein disruption were distinct. This suggests that A-T fibroblasts have adapted to the loss of ATM and have alternative mechanisms to initiate SCE.
White
Jason S
JS
Department of Radiation Oncology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, Pittsburgh, PA 15213-1863, USA.
Choi
Serah
S
Bakkenist
Christopher J
CJ
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations / Q000187:drug effects / Q000528:radiation effects; D002877:Chromosomes, Human / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology*; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases