Paper ID: 60
1 University of Toronto (Canada)
2 University of Western Ontario (Canada)
As Programmed Cell Death (PCD) acts in opposition to the fitness of the cell executing it, how PCD came about during evolution remains a quandary. A logical hypothesis is that cells capacities for self-killing must have co-opted processes that originally promoted cell survival. We have discovered what might be regarded as a living fossil of PCD that illuminates this hypothesis. Yeast sporulation involves a 5-way cell division, with the 4 meiotic products developing within the remnant of the cell that produced them. We showed that PCD of this remnant occurs as an intrinsic aspect of yeast gametogenesis and is executed through developmentally programmed vacuolar rupture. Intriguingly, undeveloped meiotic nuclei that are frequently swept up in this PCD are subjected to fragmentation of their genomic DNA into nucleosomal ladders, a hallmark of apoptosis. This phenomenon is dependent on NUC1, the yeast homolog of mitochondrial endonuclease G, and is associated with mitochondrial membrane depolarization in the remnant cell that occurs prior to vacuolar rupture. Despite being a prominent feature of apoptosis, the raison d’être for genome fragmentation during mammalian apoptosis remains unknown. Similarly, the underlying role of this DNA fragmentation pathway during yeast meiotic PCD has remained obscure. Yeast possesses numerous viral entities whose persistence requires successful meiotic transmission. We have now determined that NUC1 functions in a rudimentary apoptotic pathway that promotes yeast survival through an innate immune defense against these viral entities. Accumulating L-A and “Killer” dsRNA viruses that are endemic to yeast triggers the release of Nuc1 through an apparent MOMP-like (mitochondrial outer membrane permeabilization) phenomenon, resulting in their downregulation. Failure of Nuc1 to curb the accumulation of the Killer virus causes lethality in mitotic cells. Molecular, biochemical, and genetic analysis confirms that accumulating Killer virus within the cells causes this lethality, illuminating that this rudimentary apoptotic pathway therefore functions in an innate immune capacity. Extension of these findings to meiotic cells confirms that NUC1 prevents the hyper-accumulation of Killer toxin following meiosis. We are interested in the roles this pathway may play for defense of the yeast germline against other genetic parasites such as retrotrasnposons.