Identification of genes required for protection from doxorubicin by a genome-wide screen in Saccharomyces cerevisiae.
Anthracyclines are chemotherapeutic agents commonly used to treat a broad range of malignancies. Although effective, these drugs present serious complications, most notably cardiotoxicity. To determine the mechanisms that mediate cytoprotection from doxorubicin, we have screened the collection of Saccharomyces cerevisiae haploid gene deletion mutants. We have identified 71 deletion strains that display varying degrees of hypersensitivity to doxorubicin at a concentration that does not significantly reduce the viability of wild-type cells. Complementation of the doxorubicin-sensitive phenotype of the deletion strains with the wild-type genes proves that the sensitivity of the strain to doxorubicin is due to the gene deletion. The genes that mediate cytoprotection from doxorubicin belong to multiple pathways including DNA repair, RNA metabolism, chromatin remodeling, amino acid metabolism, and heat shock response. In addition, proteins with mitochondrial, osmosensing, vacuolar, and ribosomal functions are also required for protection from doxorubicin. We tested the sensitivity of the deletion strains to other cytotoxic agents, which resulted in different drug-specific sensitive groups. Most of the identified genes have mammalian homologues that participate in conserved pathways. Our data may prove useful to develop strategies aimed at sensitizing tumor cells to doxorubicin as well as protecting cardiac cells from its cytotoxic effects.
Xia
Ling
L
Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, CB-2803, Augusta, GA 30912, USA.
Jaafar
Lahcen
L
Cashikar
Anil
A
Flores-Rozas
Hernan
H
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D019610:Cytoprotection; D004317:Doxorubicin / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D005816:Genetic Complementation Test; D016681:Genome, Fungal; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin