Identification of Genes Required for Protection from Doxorubicin by a Genome-Wide Screen in Saccharomyces cerevisiae

Abstract

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 doxorubicinsensitive 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. [Cancer Res 2007;67(23):11411-8]

The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer

“…SWI/SNF mutations also cause increased sensitivity to DNA-damaging agents, including hydroxyurea, cisplatin, methyl methanesulfonate, and UV-light (Birrell et al 2001; Chai et al 2005; Xia et al 2007). These defects may arise because SWI/SNF subunits have roles in nucleotide excision repair (Gong et al 2006), and DNA double-strand break (DSB) repair through the homologous recombination (HR) pathway (Chai et al 2005).…”

“…These defects may arise because SWI/SNF subunits have roles in nucleotide excision repair (Gong et al 2006), and DNA double-strand break (DSB) repair through the homologous recombination (HR) pathway (Chai et al 2005). SWI/SNF defective cells also show increased sensitivity to the topoisomerase II inhibitor daunorubicin (Xia et al 2007). …”

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

“…A total of 71 deletion strains displayed varying levels of sensitivity to anthracyclines [15]. Of these, several factors involved in the heat-shock response (HSR) were identified, including the heat shock protein 40 ( HSP40 ) Ydj1p and Zuo1p, the HSP70 Ssz1p and New1p, until then of unknown function.…”

Type 2C Protein Phosphatases in Fungi

“…Further links between Ptc1 and mitochondrial function come from the observations that in a gem3 background (lacking a protein of the Rho family needed to maintain mitochondrial tubular morphology), deletion of PTC1 causes significant growth defects (20). Mitochondrial instability of the ptc1 mutant has been proposed as the reason for its sensitivity to the antitumor drug doxorubicin (111).…”