Genome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets

Genetic interactions reveal insights into cellular function and can be used to identify drug targets. Here we construct a new model to predict negative genetic interactions in protein complexes by exploiting the evolutionary history of genes in parallel converging pathways in metabolism. We evaluate our model with protein complexes of Saccharomyces cerevisiae and show that the predicted protein pairs more frequently have a negative genetic interaction than random proteins from the same complex. Furthermore, we apply our model to human protein complexes to predict novel cancer drug targets, and identify 20 candidate targets with empirical support and 10 novel targets amenable to further experimental validation. Our study illustrates that negative genetic interactions can be predicted by systematically exploring genome evolution, and that this is useful to identify novel anti-cancer drug targets.

[1]  M. P. Cummings,et al.  PAUP* Phylogenetic analysis using parsimony (*and other methods) Version 4 , 2000 .

[2]  Jennifer M. Rust,et al.  The BioGRID Interaction Database , 2011 .

[3]  C. Schilling,et al.  Flux coupling analysis of genome-scale metabolic network reconstructions. , 2004, Genome research.

[4]  Philip Lijnzaad,et al.  A consensus of core protein complex compositions for Saccharomyces cerevisiae. , 2010, Molecular cell.

[5]  U. Weidle,et al.  Synthetic lethality-based targets for discovery of new cancer therapeutics. , 2011, Cancer genomics & proteomics.

[6]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[7]  M. Yaffe,et al.  Exploiting synthetic lethal interactions for targeted cancer therapy , 2009, Cell cycle.

[8]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[9]  Jason H. Moore,et al.  The Ubiquitous Nature of Epistasis in Determining Susceptibility to Common Human Diseases , 2003, Human Heredity.

[10]  Jim Thurmond,et al.  FlyBase 101 – the basics of navigating FlyBase , 2011, Nucleic Acids Res..

[11]  B. Clurman,et al.  The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Xiangxue Wang.  An Integrative Multi-Network and Multi-Classifier Approach to Predict Genetic Interactions , 2015 .

[13]  T. Ideker,et al.  Differential network biology , 2012, Molecular systems biology.

[14]  Kevin R Brown,et al.  Essential gene profiles in breast, pancreatic, and ovarian cancer cells. , 2012, Cancer discovery.

[15]  Bas E Dutilh,et al.  Asymmetric relationships between proteins shape genome evolution , 2009, Genome Biology.

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

[17]  Grant W. Brown,et al.  Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , 2007, Nature.

[18]  Sean R. Collins,et al.  Exploration of the Function and Organization of the Yeast Early Secretory Pathway through an Epistatic Miniarray Profile , 2005, Cell.

[19]  Andrei L. Turinsky,et al.  A Census of Human Soluble Protein Complexes , 2012, Cell.

[20]  Monica L. Mo,et al.  Global reconstruction of the human metabolic network based on genomic and bibliomic data , 2007, Proceedings of the National Academy of Sciences.

[21]  Tetsu Akiyama,et al.  The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells , 2004, Development.

[22]  Shan Zhao,et al.  Mining protein networks for synthetic genetic interactions , 2008, BMC Bioinformatics.

[23]  Sean R. Collins,et al.  Functional Organization of the S. cerevisiae Phosphorylation Network , 2009, Cell.

[24]  I. Dragoni,et al.  The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability , 2009, The Journal of cell biology.

[25]  Ian H. Witten,et al.  The WEKA data mining software: an update , 2009, SKDD.

[26]  S. Oliver,et al.  An integrated approach to characterize genetic interaction networks in yeast metabolism , 2011, Nature Genetics.

[27]  Julia Tischler,et al.  The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene , 2003, Molecular and Cellular Biology.

[28]  Gary D Bader,et al.  The Genetic Landscape of a Cell , 2010, Science.

[29]  Adam Frost,et al.  Functional Repurposing Revealed by Comparing S. pombe and S. cerevisiae Genetic Interactions , 2012, Cell.

[30]  I. Ial,et al.  Nature Communications , 2010, Nature Cell Biology.

[31]  L. Chin,et al.  Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer , 2012, Nature.

[32]  J. Nichols,et al.  The RNA–Methyltransferase Misu (NSun2) Poises Epidermal Stem Cells to Differentiate , 2011, PLoS genetics.

[33]  B. Clurman,et al.  FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation , 2008, Nature Reviews Cancer.

[34]  J. Fernández,et al.  A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. , 1999, Genes & development.

[35]  Christian von Mering,et al.  STRING 7—recent developments in the integration and prediction of protein interactions , 2006, Nucleic Acids Res..

[36]  Dmitrij Frishman,et al.  MIPS: analysis and annotation of proteins from whole genomes in 2005 , 2005, Nucleic Acids Res..

[37]  D. O’Carroll,et al.  Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression , 2002, The EMBO journal.

[38]  Sean R. Collins,et al.  A genetic interaction map of RNA-processing factors reveals links between Sem1/Dss1-containing complexes and mRNA export and splicing. , 2008, Molecular cell.

[39]  Wolfgang Huber,et al.  Mapping of signaling networks through synthetic genetic interaction analysis by RNAi , 2011, Nature Methods.

[40]  Curt Wittenberg,et al.  An essential G1 function for cyclin-like proteins in yeast , 1989, Cell.

[41]  D. Swofford.  PAUP*: Phylogenetic analysis using parsimony (*and other methods), Version 4.0b10 , 2002 .

[42]  U. Sauer,et al.  Metabolic functions of duplicate genes in Saccharomyces cerevisiae. , 2005, Genome research.

[43]  N. Katsanis,et al.  Human genetics and disease: Beyond Mendel: an evolving view of human genetic disease transmission , 2002, Nature Reviews Genetics.

[44]  Robert P. St.Onge,et al.  Defining genetic interaction , 2008, Proceedings of the National Academy of Sciences.

[45]  J. Hurley,et al.  Molecular Architecture and Functional Model of the Complete Yeast ESCRT-I Heterotetramer , 2007, Cell.

[46]  Ron Shamir,et al.  A plasma-membrane E-MAP reveals links of the eisosome with sphingolipid metabolism and endosomal trafficking , 2010, Nature Structural &Molecular Biology.

[47]  D. Eisenberg,et al.  Use of Logic Relationships to Decipher Protein Network Organization , 2004, Science.

[48]  F. Watt,et al.  The RNA Methyltransferase Misu (NSun2) Mediates Myc-Induced Proliferation and Is Upregulated in Tumors , 2006, Current Biology.

[49]  Markus Babst,et al.  Efficient cargo sorting by ESCRT-I and the subsequent release of ESCRT-I from multivesicular bodies requires the subunit Mvb12. , 2006, Molecular biology of the cell.

[50]  Sourav Bandyopadhyay,et al.  Rewiring of Genetic Networks in Response to DNA Damage , 2010, Science.

[51]  V. Godfrey,et al.  Functional Redundancy of SWI/SNF Catalytic Subunits in Maintaining Vascular Endothelial Cells in the Adult Heart , 2012, Circulation research.

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

[53]  Akinobu Matsumoto,et al.  Fbxw7-dependent Degradation of Notch Is Required for Control of “Stemness” and Neuronal-Glial Differentiation in Neural Stem Cells* , 2011, The Journal of Biological Chemistry.

[54]  Nevan J Krogan,et al.  Epistatic relationships reveal the functional organization of yeast transcription factors , 2010, Molecular systems biology.

[55]  Hans-Werner Mewes,et al.  CORUM: the comprehensive resource of mammalian protein complexes , 2007, Nucleic Acids Res..

[56]  Ji Han Kim,et al.  A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. , 2011, Human molecular genetics.

[57]  D. Katzmann,et al.  Mvb12 is a novel member of ESCRT-I involved in cargo selection by the multivesicular body pathway. , 2006, Molecular biology of the cell.

[58]  Lin Geng,et al.  A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation , 2011, Nature Genetics.

[59]  S. L. Wong,et al.  Combining biological networks to predict genetic interactions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Kim Nasmyth,et al.  Positive feedback in the activation of Gl cyclins in yeast , 1991, Nature.

[61]  Kara Dolinski,et al.  The BioGRID Interaction Database: 2011 update , 2010, Nucleic Acids Res..

[62]  S. Oliver,et al.  Plasticity of genetic interactions in metabolic networks of yeast , 2007, Proceedings of the National Academy of Sciences.

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