The role of SNM1 family nucleases in etoposide-induced apoptosis

DNA double strand breaks (DSBs) induced by etoposide, an inhibitor of DNA topoisomerase II, are repaired mainly by non-homologous end joining (NHEJ). Unexpectedly, it was found that at high doses of etoposide, proteins involved in NHEJ, such as KU70/80, DNA-PKcs and ARTEMIS/SNM1C, trigger apoptosis rather than repair of DSBs. Because ARTEMIS is a member of the SNM1 protein family that includes SNM1A and APOLLO/SNM1B, this study examined whether SNM1A and/or APOLLO are also involved in etoposide-induced apoptosis. Using SNM1A−/− and APOLLO−/− cells, it was found that both SNM1A and APOLLO participate in etoposide-induced apoptosis. Although cell viability monitored by MTT assay did not differ between SNM1A−/−/APOLLO−/−/ARTEMIS−/−, SNM1A−/−/APOLLO−/−, and single gene knockout cells, DNA fragmentation monitored by TUNEL assay differed between these cells, suggesting that the three SNM1 family nucleases function independently, at least during the induction of apoptotic DNA fragmentation.

► Both SNM1A and APOLLO are necessary for etoposide-induced apoptosis as demonstrated using SNM1A−/− and APOLLO−/− knockout cells. ► SNM1A and APOLLO act before mitochondria and caspase activation during apoptosis. ► SNM1A, APOLLO and ARTEMIS seem to function in apoptotic DNA fragmentation, as shown using SNM1A−/−/APOLLO−/−/ARTEMIS−/− triple gene knockout cells.