The human ether-a-go-go-related gene (HERG) encodes a delayed rectifier Kchannel, which isexpressed in a variety of tissues and cells. Besides its well-recognized function in cellular electro-physiology, HERG channels have also been im-plicated in neuronal differentiation and cell cycle regu-lation. We have recently found that HERG regulates apoptosis. To elucidate the signaling pathways, we performed studies in HEK293 cells stably expressing ERG channels. ELISA was used to quantify DNA fragmentation, a biochemical hallmark of apoptosis. In HERG-transfected HEK cells, the degree of DNA fragmentation was found consistently higher (4-times) than in non-transfected cells. Correspondingly, remarkable activation of caspase 3, caspase 9 and cleavage of PARP were seen in HERG-expressing cells, which were otherwise minimal in non-transfected cells. Exposure of cells to H2O2 (10 hrs) at concentrations up to 1 mM, which is known to induce apoptosis in a variety of cells, caused minimal DNAfragmentation in non-transfected cells. HERG expression facilitates DNA fragmentation induced by H2O2 at a concentration-dependent fashion, starting at 200