Endonuclease G is an apoptotic DNase when released from mitochondria

Nucleosomal fragmentation of DNA is a hallmark of apoptosis (programmed cel l death)(1), and results from the activation of nucleases in cells undergoi ng apoptosis. One such nuclease, DNA fragmentation factor (DFF, a caspase-a ctivated deoxyribonuclease (CAD) and its inhibitor (ICAD)), is capable of i nducing DNA fragmentation and chromatin condensation after cleavage by casp ase-3 (refs 2-4). However, although transgenic mice lacking DFF45 or its ca spase cleavage site have significantly reduced DNA fragmentation(5,6), thes e mice still show residual DNA fragmentation and are phenotypically normal( 5-7). Here we report the identification and characterization of another nuc lease that is specifically activated by apoptotic stimuli and is able to in duce nucleosomal fragmentation of DNA in fibroblast cells from embryonic mi ce lacking DFF. This nuclease is endonuclease G (endoG), a mitochondrion-sp ecific nuclease that translocates to the nucleus during apoptosis. Once rel eased from mitochondria, endoG cleaves chromatin DNA into nucleosomal fragm ents independently of caspases. Therefore, endoG represents a caspase-indep endent apoptotic pathway initiated from the mitochondria.