Probing the evolutionary origins of apoptosis.

点击翻译按钮获取中文摘要

Because they act in direct opposition to cell survival, the question of how programmed cell death mechanisms might have first evolved has for long been a mystery. The discovery of apparent cell death pathways acting in single celled microbes has served to deepen this paradox. Indeed, although the bona fide biological functions for these pathways has remained unclear, in the budding yeast Saccharomyces cerevisiae, death pathways utilize conserved cell-killing machinery known to act in metazoans. We hypothesized that yeast might utilize some of these "killing pathways" for non cell-death related functions. We have recently described a novel aspect of the yeast lifecycle functioning during its gametogenesis phase (more commonly known as sporulation) which we have named "sporoptosis". Yeast sporoptosis involves complimentary cell death-related pathways that converge to accomplish the destruction of unpackaged meiotic nuclei. While our first paper describing sporoptosis extensively characterized the function of a vacuolar/autophagic pathway, we also provided strong evidence supporting the existence of a mitochondrial pathway related to mammalian apoptosis that acts at least partly in parallel. Specifically, we found that during sporoptosis, the nuclear genome of unpackaged nuclei is fragmented into nucleosomal ladders, a long-acknowledged hallmark of mammalian apoptosis. Moreover, sporoptotic genome fragmentation requires the function of an ortholog of endonuclease G, an ancient mitochondrial protein which also functions to accomplish the homologous event during mammalian apoptosis. In this proposal, I describe preliminary results that further illuminate the functions of the endoG/mitochondrial pathway during yeast gametogenesis, and experiments designed to advance our understanding of this pathway. Our studies have important implications for the evolution of cell death mechanisms.