Inference of Protein Complex Activities from Chemical-Genetic Profile and Its Applications: Predicting Drug-Target Pathways

The chemical-genetic profile can be defined as quantitative values of deletion strains' growth defects under exposure to chemicals. In yeast, the compendium of chemical-genetic profiles of genomewide deletion strains under many different chemicals has been used for identifying direct target proteins and a common mode-of-action of those chemicals. In the previous study, valuable biological information such as protein–protein and genetic interactions has not been fully utilized. In our study, we integrated this compendium and biological interactions into the comprehensive collection of ∼490 protein complexes of yeast for model-based prediction of a drug's target proteins and similar drugs. We assumed that those protein complexes (PCs) were functional units for yeast cell growth and regarded them as hidden factors and developed the PC-based Bayesian factor model that relates the chemical-genetic profile at the level of organism phenotypes to the hidden activities of PCs at the molecular level. The inferred PC activities provided the predictive power of a common mode-of-action of drugs as well as grouping of PCs with similar functions. In addition, our PC-based model allowed us to develop a new effective method to predict a drug's target pathway, by which we were able to highlight the target-protein, TOR1, of rapamycin. Our study is the first approach to model phenotypes of systematic deletion strains in terms of protein complexes. We believe that our PC-based approach can provide an appropriate framework for combining and modeling several types of chemical-genetic profiles including interspecies. Such efforts will contribute to predicting more precisely relevant pathways including target proteins that interact directly with bioactive compounds.

[1]  J. Diffley,et al.  A central role for DNA replication forks in checkpoint activation and response. , 2003, Molecular cell.

[2]  K. Siegers,et al.  A novel protein complex promoting formation of functional α‐ and γ‐tubulin , 1998, The EMBO journal.

[3]  Chiara Sabatti,et al.  Network component analysis: Reconstruction of regulatory signals in biological systems , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Arno,et al.  Genomic Screening in Vivo Reveals the Role Played by Vacuolar H+ ATPase and Cytosolic Acidification in Sensitivity to DNA-Damaging Agents Such as Cisplatin , 2007, Molecular Pharmacology.

[5]  A. Koller,et al.  PRLLLSLAEQ GVLPKCLAYV DRNGRPLLCF FVSLVFGCIG FVATSDAEEQ SRTLCSMAHQ GLIPWWFGYI DRAGRPLVGI MANSLFGLLA FLVKSGSMSE SRILFGLSKN KLAPKFLSRT TKGGVPYIAV FVTAAFGALA YMETSTGGDK SRTMVALAEQ RFLPEIFSYV DRKGRPLVGI AVTSAFGLIA FVAASKKEGE SRCMVAMAHI GNLPKFLNRV DKRGRPMNAI LLTLFFGLLS FVAASDKQAE SRVLYSLART GNAPKQFGYV TRQ , 2022 .

[6]  A. Schmidt,et al.  HEAT Repeats Mediate Plasma Membrane Localization of Tor2p in Yeast* , 2000, The Journal of Biological Chemistry.

[7]  M. Bjornsti,et al.  The tor pathway: a target for cancer therapy , 2004, Nature Reviews Cancer.

[8]  Michael Hampsey,et al.  A Review of Phenotypes in Saccharomyces cerevisiae , 1997, Yeast.

[9]  Mike Tyers,et al.  BioGRID: a general repository for interaction datasets , 2005, Nucleic Acids Res..

[10]  Hilla Peretz,et al.  The , 1966 .

[11]  Tianwei Yu,et al.  Inference of transcriptional regulatory network by two-stage constrained space factor analysis , 2005, Bioinform..

[12]  Grant W. Brown,et al.  Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways , 2004, Nature Biotechnology.

[13]  Jill P. Mesirov,et al.  GeneCluster 2.0: an advanced toolset for bioarray analysis , 2004, Bioinform..

[14]  Alok J. Saldanha,et al.  Java Treeview - extensible visualization of microarray data , 2004, Bioinform..

[15]  B. Alberts.  The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists , 1998, Cell.

[16]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[17]  Angus Chen,et al.  Conjugation of Nedd8 to CUL1 Enhances the Ability of the ROC1-CUL1 Complex to Promote Ubiquitin Polymerization* , 2000, The Journal of Biological Chemistry.

[18]  Charles Boone,et al.  A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes required for S phase progression in the presence of DNA damage , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Chiara Sabatti,et al.  Bayesian sparse hidden components analysis for transcription regulation networks , 2005, Bioinform..

[20]  S. Schmid,et al.  Clathrin-coated vesicle formation and protein sorting: an integrated process. , 1997, Annual review of biochemistry.

[21]  C. Haanen,et al.  Mitochondrial biogenesis and mitochondrial activity during the progression of the cell cycle of human leukemic cells. , 1988, Experimental cell research.

[22]  M. Krieger,et al.  Retrograde transport on the COG railway. , 2006, Trends in cell biology.

[23]  T. Toda,et al.  Covalent modifier NEDD8 is essential for SCF ubiquitin‐ligase in fission yeast , 2000, The EMBO journal.

[24]  Rafael A. Irizarry,et al.  Improved microarray methods for profiling the yeast knockout strain collection , 2005, Nucleic acids research.

[25]  B. Regenberg,et al.  The permease homologue Ssy1p controls the expression of amino acid and peptide transporter genes in Saccharomyces cerevisiae , 1998, Molecular microbiology.

[26]  C. Ong,et al.  Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway , 2005, Cellular and Molecular Life Sciences CMLS.

[27]  Rafael A Irizarry,et al.  Global synthetic-lethality analysis and yeast functional profiling. , 2006, Trends in genetics : TIG.

[28]  J. Heitman,et al.  FKBP12‐rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol‐4 kinase activity. , 1995, The EMBO journal.

[29]  S. Munro,et al.  The Sec34/35 Golgi transport complex is related to the exocyst, defining a family of complexes involved in multiple steps of membrane traffic. , 2001, Developmental cell.

[30]  Dong Wang,et al.  Cellular processing of platinum anticancer drugs , 2005, Nature Reviews Drug Discovery.

[31]  Sean R. Collins,et al.  Global landscape of protein complexes in the yeast Saccharomyces cerevisiae , 2006, Nature.

[32]  Robbie Loewith,et al.  The TOR signalling network from yeast to man. , 2006, The international journal of biochemistry & cell biology.

[33]  M. Roberge,et al.  Yeast as a tool to uncover the cellular targets of drugs , 2006, Biotechnology journal.

[34]  P. Bork,et al.  Proteome survey reveals modularity of the yeast cell machinery , 2006, Nature.

[35]  Yves Pommier,et al.  Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints. , 2004, Current medicinal chemistry. Anti-cancer agents.

[36]  J. Heitman,et al.  The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae , 1993, Molecular and cellular biology.

[37]  S. C. Falco,et al.  Single amino acid substitutions in the enzyme acetolactate synthase confer resistance to the herbicide sulfometuron methyl. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Snyder,et al.  Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Tomida,et al.  Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex , 2004, Cancer Research.

[40]  Inmar E. Givoni,et al.  Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast , 2006, Cell.

[41]  S. Emr,et al.  TRAPPII subunits are required for the specificity switch of a Ypt–Rab GEF , 2006, Nature Cell Biology.

[42]  J. C. Hinshaw,et al.  Discovering Modes of Action for Therapeutic Compounds Using a Genome-Wide Screen of Yeast Heterozygotes , 2004, Cell.

[43]  S. Jentsch,et al.  A novel protein modification pathway related to the ubiquitin system , 1998, The EMBO journal.

[44]  Michael I. Jordan,et al.  Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Boulesteix,et al.  Predicting transcription factor activities from combined analysis of microarray and ChIP data: a partial least squares approach , 2005, Theoretical Biology and Medical Modelling.

[46]  M. Bjornsti,et al.  Mechanisms of camptothecin resistance in yeast DNA topoisomerase I mutants. , 1993, The Journal of biological chemistry.

[47]  R. Knippers,et al.  Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks , 1988, Molecular and cellular biology.

[48]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[49]  Fulai Jin,et al.  Insights into TOR function and rapamycin response: chemical genomic profiling by using a high-density cell array method. , 2005, Proceedings of the National Academy of Sciences of the United States of America.