The Role of Protein Chaperones in The Survival From Anthracycline-Induced Oxidative Stress in Saccharomyces Cerevisiae

• Type of Material: Article
• Authors: Jana S. Miles, Florida A&M University; Samantha J. Sojourner, Florida A&M University; Lahcen Jaafar, Emory University; Aurellia Whitmore, Florida A&M University; Selina Darling-Reed, Florida A&M University; Hernan Flores-Rozas, Florida A&M University
• Language: English
• Date: 2018-03
• Publisher: IJAR
• Publication Version: Final Published Version
• Copyright Statement: Copy Right, IJAR, 2018,. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.journalijar.com/current-issue/?mn=03&yr=2018
• Title of Journal or Parent Work: International Journal of Advanced Research
• Volume: 6
• Issue: 3
• Start Page: 144
• End Page: 152
• Grant/Funding Information: This project was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant G12MD007582 and P20MD006738.
• Keywords: Cancer; Molecular Chaperones; Oxidative Stress; Anthracyclines; Heat-Shock Response
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology; Chemistry, Pharmaceutical

Abstract

Several S. cerevisiae 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 ydj1Δ, ssz1Δ and zuo1Δ mutants. In addition, new1Δ, 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 rad52Δ, 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 hsp104Δ 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 S. cerevisiae, doxorubicin produces protein aggregation through ROS and requires Ydj1p and New1p for resolution.