Caffeine-induced radiosensitization is independent of nonhomologous end joining of DNA double-strand breaks.
After exposure to ionizing radiation, proliferating cells actively slow down progression through the cell cycle through the activation of checkpoints to provide time for repair. Two major complementary DNA double-strand break (DSB) repair pathways exist in mammalian cells, homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). The relationship between checkpoint activation and these two types of DNA DSB repair pathways is not clear. Caffeine, as a nonspecific inhibitor of ATM and ATR, abolishes multi-checkpoint responses and sensitizes cells to radiation-induced killing. However, it remains unknown which DNA repair process, NHEJ or HRR, or both, is affected by caffeine-abolished checkpoint responses. We report here that caffeine abolishes the radiation-induced G(2)-phase checkpoint and efficiently sensitizes both NHEJ-proficient and NHEJ-deficient mammalian cells to radiation-induced killing without affecting NHEJ. Our results indicate that caffeine-induced radiosensitization occurs by affecting an NHEJ-independent process, possibly HRR.
Wang
Xiang
X
Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Wang
Huichen
H
Iliakis
George
G
Wang
Ya
Y
D000818:Animals; D016466:CHO Cells; D002110:Caffeine / Q000494:pharmacology*; D002449:Cell Aggregation; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects*; D004586:Electrophoresis; D005347:Fibroblasts; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000187:drug effects* / Q000528:radiation effects; D013997:Time Factors
D010726:Phosphodiesterase Inhibitors; D002110:Caffeine