Probing the evolutionary origins of apoptosis.

由于它们的作用与细胞存活直接相反，因此程序性细胞死亡机制最初是如何进化的问题长期以来一直是一个谜。在单细胞微生物中作用的明显细胞死亡途径的发现加深了这一矛盾。事实上，尽管这些途径的真正生物学功能仍不清楚，但在芽殖酵母酿酒酵母中，死亡途径利用已知在后生动物中起作用的保守细胞杀伤机制。我们假设酵母可能利用这些“杀伤途径”中的一些来实现非细胞死亡相关的功能。我们最近描述了一个新的方面，酵母生命周期的功能，在其配子发生阶段（更常见的称为孢子形成），我们已经命名为“孢子”。酵母孢子凋亡涉及互补的细胞死亡相关途径，这些途径会聚以完成未包装的减数分裂核的破坏。虽然我们的第一篇论文描述了孢子凋亡广泛的特点空泡/自噬途径的功能，我们也提供了强有力的证据支持存在的线粒体途径与哺乳动物细胞凋亡，至少部分平行的行为。具体来说，我们发现，在孢子凋亡，未包装的细胞核的核基因组被分割成核小体梯，一个长期公认的哺乳动物细胞凋亡的标志。此外，sporoptotic基因组片段化需要核酸内切酶G的直系同源物的功能，核酸内切酶G是一种古老的线粒体蛋白，其也起作用以在哺乳动物细胞凋亡期间完成同源事件。在这个建议中，我描述了初步的结果，进一步阐明了酵母配子发生过程中的endoG/线粒体途径的功能，以及旨在促进我们对这一途径的理解的实验。我们的研究对细胞死亡机制的进化具有重要意义。

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.