CIDE, A NOVEL FAMILY OF CELL-DEATH ACTIVATORS WITH HOMOLOGY TO THE 45KDA SUBUNIT OF THE DNA FRAGMENTATION FACTOR

DFF45 is a subunit of the DNA fragmentation factor (DFF) that is cleav ed by caspase-3 during apoptosis. However, the mechanism by which DFF4 5 regulates apoptotic cell death remains poorly understood. Here we re port the identification and characterization of two mammalian genes, C IDE-A and CIDE-B, encoding highly related proteins with homology to th e N-terminal region of DFF45. CIDE-A and CIDE-B were found to activate apoptosis in mammalian cells, which was inhibited by DFF45 but not by caspase inhibitors, Expression of CIDE-A induced DNA fragmentation in 293T cells, which was inhibited by DFF45, further suggesting that DFF 45 inhibits the apoptotic activities of CIDEs, In addition to mammalia n CIDE-A and CIDE-B, we identified DREP-1, a Drosophila melanogaster h omolog of DFF45 that could inhibit CIDE-A-mediated apoptosis. Mutant a nalysis revealed that the C-terminal region of CIDE-A was necessary nd sufficient for killing whereas the region with homology to DFF45 loca ted in the N-terminus was required for DFF45 to inhibit CIDE-A-induced apoptosis. CD95/Fas-mediated apoptosis was enhanced by CIDEs but inhi bited by DFF45, These studies suggest that DFF45 is evolutionarily con served and implicate CIDEs as DFF45-inhibitable effectors that promote cell death and DNA fragmentation.