Genome-wide screen identifies genes whose inactivation confer resistance to cisplatin in Saccharomyces cerevisiae

To identify novel genes that mediate cellular resistance to cisplatin, we have screened the collection of Saccharomyces cerevisiae deletion strains. We have found reproducibly 22 genes/open reading frames (ORF), which when deleted, confer resistance to cisplatin at a concentration that is lethal to...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-07, Vol.65 (13), p.5890-5897
Main Authors: HUANG, Ruea-Yea, EDDY, Martha, VUJCIC, Marija, KOWALSKI, David
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Camptothecin - pharmacology
Cisplatin - pharmacology
Doxorubicin - pharmacology
Drug Resistance, Microbial - genetics
Fluorouracil - pharmacology
Gene Deletion
Gene Silencing
Genome, Fungal
Medical sciences
Methylnitronitrosoguanidine - pharmacology
Open Reading Frames
Pharmacology. Drug treatments
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - genetics
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Summary:To identify novel genes that mediate cellular resistance to cisplatin, we have screened the collection of Saccharomyces cerevisiae deletion strains. We have found reproducibly 22 genes/open reading frames (ORF), which when deleted, confer resistance to cisplatin at a concentration that is lethal to wild-type cells. Complementation of individual deletion strains with the corresponding wild-type gene abolished cisplatin resistance, confirming that specific gene deletions caused the resistance. Twenty of the genes/ORFs identified have not been previously linked to cisplatin resistance and belong to several distinct functional groups. Major functional groups encode proteins involved in nucleotide metabolism, mRNA catabolism, RNA-polymerase-II-dependent gene regulation and vacuolar transport systems. In addition, proteins that function in ubiquitination, sphingolipid biogenesis, cyclic AMP-dependent signaling, DNA repair, and genome stability are also associated with cisplatin resistance. More than half of the identified genes are known to have sequences or functional homology to mammalian counterparts. Some deletion strains are cross-resistant to selected cytotoxic agents whereas hypersensitive to others. The sensitivity of certain resistant strains to other cytotoxic agents suggests that our findings may point to particular drug combinations that can overcome resistance caused by inactivation of specific genes.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-4093