Chemical-Genetic Interactions of Constituents in Cells Deficient for the DNA Repair Endonuclease Appear Linked to Vacuolar Disruption.

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for extracts to limit proliferation and promote an apoptosis-like event in deleted yeast was not elucidated. Our current analysis has revealed that extracts have the capacity to promote mutations in ∆ cells. In addition, the effects of extracts on ∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from identified a chemical-genetic interaction between bacopasaponin C and ∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.