Novel functions of the phosphatidylinositol metabolic pathway discovered by a chemical genomics screen with wortmannin.
We report a novel connection between the phosphatidylinositol (PI) metabolic pathway and the DNA replication and damage checkpoint pathway discovered from an unbiased chemical genomics screen. Substrates and products of PI kinases are important signaling molecules that affect a wide range of biological processes. The full collection of yeast deletion strains was screened to identify genes that confer altered sensitivity to the natural product wortmannin, a PI kinase inhibitor. These experiments have allowed us to explore metabolomic and proteomic implications of PI synthesis and turnover. This study also uncovers other biological processes affected by wortmannin treatment, including proteasome-mediated degradation and chromatin remodeling. Bioinformatic analyses were used to reveal the relative distances among cellular processes affected by wortmannin and protein-protein interactions in the wortmannin-sensitive proteomic subnetwork. These results illustrate the great utility of using a whole-genome approach in annotating the biological effects of small molecules and have clear implications for pharmacogenomics. Furthermore, our discovery points to a route to overcoming genome instability, a result of defective DNA damage signaling/repair and a hallmark of cancer.
Zewail
Amani
A
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Xie
Michael W
MW
Xing
Yi
Y
Lin
Lan
L
Zhang
P Fred
PF
Zou
Wei
W
Saxe
Jonathan P
JP
Huang
Jing
J
D000730:Androstadienes / Q000494:pharmacology*; D004249:DNA Damage; D004261:DNA Replication; D025141:Drug Resistance, Fungal / Q000235:genetics; D017353:Gene Deletion; D005800:Genes, Fungal / Q000187:drug effects; D005816:Genetic Complementation Test; D023281:Genomics / Q000379:methods*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016366:Open Reading Frames; D010716:Phosphatidylinositols / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D010716:Phosphatidylinositols; D029701:Saccharomyces cerevisiae Proteins; D000077191:Wortmannin