SCOP Means Structure

The activation of apoptotic cascades triggers a series of events, one of which is the condensation and fragmentation of chromosomal DNA.In mammals, at least three proteins have been implicated in this process -DFF40/CAD, the apoptosis-inducing factor (AIF) and a mitochondrial endonuclease termed endonuclease G (EndoG).How do these proteins work, and are their pro-apoptotic functions conserved in other species?These are the questions tackled by Ding Xue and colleagues, who report their results in Science.The authors started by cloning wah-1, which is the Caenorhabditis elegans homologue of AIF.They then examined the effects of inhibiting the expression of wah-1 using RNA-mediated interference (RNAi) and found that, in wah-1(RNAi)-treated worms, the appearance of embryonic cell corpses during normal development was delayed.This phenotype is similar to that observed in cps-6 mutant worms (CPS-6 is the worm orthologue of mammalian EndoG), and so indicates a role for WAH-1 in the progression of apoptosis.However, a cps-6 mutation did not enhance the wah-1(RNAi) phenotype, indicating that WAH-1 and CPS-6 might function in the same pathway.Xue and co-workers next used TUNEL assays to show that, like AIF, WAH-1 induces chromosome fragmentation.And, using a WAH-1-green fluorescent protein (GFP) fusion protein, they showed that WAH-1 localizes to the mitochondria.So how is WAH-1 activated?The release of apoptogenic factors from mitochondria in response to pro-apoptotic stimuli is triggered by so-called 'BH3-domain-only' proteins.In worms, the most upstream cell-death activator is also a BH3-domain protein, EGL-1.The authors asked whether global expression of egl-1 could release WAH-1 from the mitochondria, and they found that it couldthe punctate mitochondrial staining pattern of WAH-1-GFP became more uniformly spread throughout the cell, and more GFP fluorescence was seen in nuclei,