Selenium (Se) compounds, which are the most extensively studied cancer chemopreventive agents, induce apoptotic death of tumor cells. In the current study, we show that selenite-induced apoptosis involves DNA damage. We showed that selenite-induced apoptosis as evidenced by cleavage of poly(ADP-ribose) polymerase was reduced in NIH 3T3 cells treated with ATM small interfering RNA, suggesting the involvement of the DNA damage regulator ATM. Consistent with ATM/ATR involvement, selenite was also shown to stimulate Ser-139 phosphorylation of the ATM/ATR substrate H2AX. Selenite-induced apoptosis was shown to involve DNA topoisomerase II (Top II) as selenite-induced apoptosis was reduced in Top II-deficient HL-60/MX2 cells and in HL-60 cells co-treated with the Top II catalytic inhibitor ICRF-193. Using purified human recombinant Top II, selenite was shown to induce reversible Top II cleavage complexes in vitro. In the aggregate, these results suggest that selenite-induced apoptosis, which involves ATM/ATR and Top II, is likely to be because of DNA damage.
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