Novel functions of the phosphatidylinositol metabolic
pathway discovered by a chemical genomics screen with wortmannin
Proc Natl Acad Sci U S A 2003 Mar 18;100(6):3345-50
Novel functions of the phosphatidylinositol metabolic pathway
discovered by a chemical genomics screen with wortmannin.
Zewail A, Xie MW, Xing Y, Lin L, Zhang PF, Zou W, Saxe JP, Huang J.
Department of Molecular and Medical Pharmacology, Molecular Biology Institute,
and University of California Los Angeles-Jonsson Comprehensive Cancer Center,
David Geffen School of Medicine, University of California, Los Angeles, CA
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 signalingrepair and a hallmark of cancer.