Dicing up chromosomes: the unexpected role of Dicer in apoptosis.

4772 Cell Cycle Volume 9 Issue 24 Apoptosis is an evolutionarily conserved and tightly reglated process in which caspases, a unique family of cysteine proteases, direct the dismantling of a dying cell. A fundamental feature of apoptosis is chromosome fragmentation, which is executed by multiple apoptotic nucleases in a stepwise manner. Apoptotic nucleases first introduce 3’ hydroxyl nicks into chromosomes, which are detectable by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The 3’ hydroxyl DNA nicks are then converted into single-stranded gaps via exonuclease activity and double-stranded breaks via gap-dependent endonuclease activity, losing their TUNEL-reactive ends in the process. Generation of 3’ hydroxyl nicks in mammals is performed by 40-kD DNA fragmentation factor (DFF40). In living cells, DFF40 complexes with 45-kD DNA fragmentation factor (DFF45), a cognate inhibitor of DFF40. In dying cells, activated caspase-3 and caspase-7 cleave DFF45 to release DFF40, which initiates chromosome fragmentation by generating TUNEL-reactive DNA ends. Homologues of DFF40 or DFF45 have not been identified in the C. elegans genome. However, apoptotic factors important for resolution of TUNEL-reactive DNA ends appear to be conserved between mammals and nematodes. For example, endonuclease G (EndoG) and apoptosis-inducing factor (AIF) and their corresponding C. elegans homologues CPS-6 (CED-3 protease suppressor 6) and WAH-1 (worm AIF homologue) translocate from mitochondria to the nucleus to facilitate chromosome fragmentation and cell death. DNase II and its C. elegans homologues, Dicing up chromosomes The unexpected role of dicer in apoptosis