A genome-wide screen in Saccharomyces cerevisiae reveals pathways affected by arsenic toxicity.
We have used Saccharomyces cerevisiae to identify toxicologically important proteins and pathways involved in arsenic-induced toxicity and carcinogenicity in humans. We performed a systemic screen of the complete set of 4733 haploid S. cerevisiae single-gene-deletion mutants to identify those that have decreased or increased growth, relative to wild type, after exposure to sodium arsenite (NaAsO(2)). IC(50) values for all mutants were determined to further validate our results. Ultimately we identified 248 mutants sensitive to arsenite and 5 mutants resistant to arsenite exposure. We analyzed the proteins corresponding to arsenite-sensitive mutants and determined that they belonged to functional categories that include protein binding, phosphate metabolism, vacuolar/lysosomal transport, protein targeting, sorting, and translocation, cell growth/morphogenesis, cell polarity and filament formation. Furthermore, these data were mapped onto a protein interactome to identify arsenite-toxicity-modulating networks. These networks are associated with the cytoskeleton, ubiquitination, histone acetylation and the MAPK signaling pathway. Our studies have potential implications for understanding toxicity and carcinogenesis in arsenic-induced human conditions, such as cancer and aging.
Zhou
Xue
X
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Arita
Adriana
A
Ellen
Thomas P
TP
Liu
Xin
X
Bai
Jingxiang
J
Rooney
John P
JP
Kurtz
Adrienne D
AD
Klein
Catherine B
CB
Dai
Wei
W
Begley
Thomas J
TJ
Costa
Max
M
D018053:Arsenites / Q000494:pharmacology / Q000633:toxicity*; D025141:Drug Resistance, Fungal; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D016681:Genome, Fungal; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests / Q000379:methods; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology / Q000633:toxicity*
D018053:Arsenites; D029701:Saccharomyces cerevisiae Proteins; D017670:Sodium Compounds; C017947:sodium arsenite