Mole Evid

Downlo ptive response (AR) is a term describing resistance to ionizing radiation–induced killing or formation of nt chromosomes that is mediated by pre-exposure to low ionizing radiation doses. The mechanism of ains elusive. Because cell killing and chromosome aberration formation derive from erroneous procesf DNA double-strand breaks (DSB), AR may reflect a modulation of DSB processing by nonhomologous ining (NHEJ) or homologous recombination repair. Here, we use plasmid end-joining assays to quantify lations induced by low ionizing radiation doses to NHEJ, the dominant pathway of DSB repair in higher otes, and investigate propagation of this response through medium transfer to nonirradiated bystander ouse embryo fibroblasts were conditioned with 10 to 1000 mGy and NHEJ quantified at different times fter by challenging with reporter plasmids containing a DSB. We show robust increases in NHEJ effiin mouse embryo fibroblasts exposed to ionizing radiation >100 mGy, irrespective of reporter plasmid Human tumor cells also show AR of similar magnitude that is compromised by caffeine, an inhibitor of amage signaling acting by inhibiting ATM, ATR, and DNA-PKcs. Growth medium from pre-irradiated duces a caffeine-sensitive AR in nonirradiated cells, similar in magnitude to that seen in irradiated cells. tander cells, γH2AX foci are specifically detected in late S-G2 phase and are associated with Rad51 foci ignify the function of homologous recombination repair, possibly on DNA replication–mediated DSBs. that s The results point to enhanced NHEJ as a mechanism of AR and suggest that AR may be transmitted to bystander cells through factors generating replication-mediated DSBs. Cancer Res; 70(21); 8498–506. ©2010 AACR.