THE ROLE OF PROTEIN CHAPERONES IN THE SURVIVAL FROM ANTHRACYCLINE-INDUCED OXIDATIVE STRESS IN SACCHAROMYCES CEREVISIAE.

Several deletion strains involving heat-shock response factors were among the most sensitive mutants identified in a previous genetic screen for doxorubicin hypersensitivity. These strains included mutants. In addition, , whose function was unknown, also displayed significant sensitivity to anthracyclines. We further investigated the basis for the sensitivity of these mutants. We determined that heat-shock could partially rescue the sensitivity of the strains to doxorubicin, including the homologous recombination mutant , which is sensitive to doxorubicin-mediated DNA double strand breaks (DSBs). However, none of the heat-shock response mutants were sensitive to DSBs, but were highly sensitive to reactive oxygen species (ROS) generated by quinone-ring-containing agents, such as anthracyclines and menadione. A fluorescent-based assay indicates that doxorubicin causes protein aggregation. Interestingly, the disaggregase mutant is not sensitive to anthracyclines or menadione suggesting that Hsp104p does not play a role in disaggregating doxorubicin-induced protein aggregates. However New1p, which has been recently shown to be a novel disaggregase, is essential for cell viability after exposure to anthracyclines and menadione and it is not involved in thermotolerance. Our data suggest that in , doxorubicin produces protein aggregation through ROS and requires Ydj1p and New1p for resolution.