ATR affecting cell radiosensitivity is dependent on homologous recombination repair but independent of nonhomologous end joining.
ATR is one of the most important checkpoint proteins in mammalian cells responding to DNA damage. Cells defective in normal ATR activity are sensitive to ionizing radiation (IR). The mechanism by which ATR protects the cells from IR-induced killing remains unclear. DNA double-strand breaks (DSBs) induced by IR are critical lesions for cell survival. Two major DNA DSB repair pathways exist in mammalian cells: homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). We show that the doxycycline (dox)-induced ATR kinase dead (ATRkd) cells have the similar inductions and rejoining rates of DNA DSBs compared with cells without dox induction, although the dox-induced ATRkd cells are more sensitive to IR and have the deficient S and G(2) checkpoints. We also show that the dox-induced ATRkd cells have a lower HRR efficiency compared with the cells without dox induction. These results indicate that the effects of ATR on cell radiosensitivity are independent of NHEJ but are linked to HRR that may be affected by the deficient S and G(2) checkpoints.
Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Hongyan
H
Wang
Huichen
H
Wang
Simon N
SN
Powell
George
G
Iliakis
Ya
Y
Wang
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011836:Radiation Tolerance / Q000502:physiology*; D016196:S Phase / Q000502:physiology / Q000528:radiation effects
D018797:Cell Cycle Proteins; D004247:DNA; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004318:Doxycycline