Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity.
Mutations in the ATM kinase cause the neurodegenerative disorder ataxia telangiectasia (A-T) and affected individuals are exquisitely radiation-sensitive and cancer-prone. Cells derived from A-T individuals contain chromosome aberrations and exhibit profound cellular radiosensitivity. ATM is an apical kinase critical for the activation of cell cycle checkpoints and the induction of apoptosis in irradiated cells. However, defects in these pathways are insufficient to account for the chromosomal instability seen in A-T cells. We show here that the small molecule KU55933 can be used as a "molecular switch" to selectively and transiently inhibit ATM kinase activity in cells. We subsequently show that the cellular radiosensitization seen when ATM kinase activity is inhibited for one hour following exposure to gamma-rays, accounts for over 70% of the total cellular radiosensitization seen when ATM kinase activity is inhibited for 17 h. Finally, we show that inhibition of ATM kinase activity for one hour following exposure to irradiation doubles the number of chromosome aberrations occurring in late-S- and G(2)-, but not M-phase, cells. These observations are unexpected and suggest that irreversible chromosome damage accumulates very rapidly when ATM kinase activity is transiently inhibited following irradiation. We propose that we have revealed an essential, yet previously undescribed, role for ATM kinase in suppressing chromosomal instability.
White
Jason S
JS
Department of Radiation Oncology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
Choi
Serah
S
Bakkenist
Christopher J
CJ
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D002461:Cell Line, Transformed; D043171:Chromosomal Instability / Q000235:genetics / Q000528:radiation effects*; D019457:Chromosome Breakage / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D008938:Mitosis / Q000235:genetics / Q000528:radiation effects; D009154:Mutation / Q000235:genetics / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D016196:S Phase / Q000235:genetics / Q000528:radiation effects; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases