Caspase-Dependent Conversion of Dicer Ribonuclease into a

Chromosome fragmentation is a hallmark of apoptosis, conserved in diverse organisms. In mammals, caspases activate apoptotic chromosome fragmentation by cleaving and inactivating an apoptotic nuclease inhibitor. We report that inactivation of the Caenorhabditis elegans dcr-1 gene, which encodes the Dicer ribonuclease important for processing of small RNAs, compromises apoptosis and blocks apoptotic chromosome fragmentation. DCR-1 was cleaved by the CED-3 caspase to generate a C-terminal fragment with deoxyribonuclease activity, which produced 3 ′ hydroxyl DNA breaks on chromosomes and promoted apoptosis. Thus, caspase-mediated activation of apoptotic DNA degradation is conserved. DCR-1 functions in fragmenting chromosomal DNA during apoptosis, in addition to processing of small RNAs, and undergoes a protease-mediated conversion from a ribonuclease to a deoxyribonuclease. One of the hallmarks of apoptosis is frag-mentation of chromosomal DNA at inter-nucleosomal regions, which generates DNA fragments differing by ~180 base pairs and contributes to the irreversible cell killing process (1, 2). Multiple deoxyribonucleases (DNases) have been implicated inmediating apoptotic DNA frag-mentation, including 40-kD DNA fragmentatio