Toward accurate reconstruction of functional protein networks

Genome‐scale screening studies are gradually accumulating a wealth of data on the putative involvement of hundreds of genes/proteins in various cellular responses or functions. A fundamental challenge is to chart out the protein pathways that underlie these systems. Previous approaches to the problem have either employed a local optimization criterion, aiming to infer each pathway independently, or a global criterion, searching for the overall most parsimonious subnetwork. Here, we study the trade‐off between the two approaches and present a new intermediary scheme that provides explicit control over it. We demonstrate its utility in the analysis of the apoptosis network in humans, and the telomere length maintenance (TLM) system in yeast. Our results show that in the majority of real‐life cases, the intermediary approach provides the most plausible solutions. We use a new set of perturbation experiments measuring the role of essential genes in telomere length regulation to further study the TLM network. Surprisingly, we find that the proteasome plays an important role in telomere length regulation through its associations with transcription and DNA repair circuits.

[1]  Allan Birnbaum,et al.  Combining Independent Tests of Significance , 1954 .

[2]  Pawel Winter,et al.  Steiner problem in networks: A survey , 1987, Networks.

[3]  Yang Li,et al.  A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II , 1994, Cell.

[4]  S. Henry,et al.  Isolation and characterization of a mutant of Saccharomyces cerevisiae with pleiotropic deficiencies in transcriptional activation and repression. , 1994, Genetics.

[5]  V A Zakian,et al.  Structure, function, and replication of Saccharomyces cerevisiae telomeres. , 1996, Annual review of genetics.

[6]  Paul Tempst,et al.  RSC, an Essential, Abundant Chromatin-Remodeling Complex , 1996, Cell.

[7]  R. Weinberg,et al.  The catalytic subunit of yeast telomerase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Huber,et al.  Structure of 20S proteasome from yeast at 2.4Å resolution , 1997, Nature.

[9]  S. Reed,et al.  Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13. , 1997, Genes & development.

[10]  S. Guha,et al.  Approximation Algorithms for Directed Steiner Tree Problems , 1998 .

[11]  Sudipto Guha,et al.  Approximation algorithms for directed Steiner problems , 1999, SODA '98.

[12]  A. Ashworth,et al.  Interaction between the Product of the Breast Cancer Susceptibility Gene BRCA2 and DSS1, a Protein Functionally Conserved from Yeast to Mammals , 1999, Molecular and Cellular Biology.

[13]  J. Petrini,et al.  The Mre11-Rad50-Xrs2 Protein Complex Facilitates Homologous Recombination-Based Double-Strand Break Repair inSaccharomyces cerevisiae , 1999, Molecular and Cellular Biology.

[14]  M. Hampsey,et al.  A general requirement for the Sin3-Rpd3 histone deacetylase complex in regulating silencing in Saccharomyces cerevisiae. , 1999, Genetics.

[15]  T. Hughes,et al.  The Est3 protein is a subunit of yeast telomerase , 2000, Current Biology.

[16]  S. Evans,et al.  Positive and negative regulation of telomerase access to the telomere. , 2000, Journal of cell science.

[17]  R. Locksley,et al.  The TNF and TNF Receptor Superfamilies Integrating Mammalian Biology , 2001, Cell.

[18]  S. Hougardy,et al.  Approximation Algorithms for the Steiner Tree Problem in Graphs , 2001 .

[19]  Ioannis Xenarios,et al.  DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions , 2002, Nucleic Acids Res..

[20]  S. Teng,et al.  Est1p As a Cell Cycle-Regulated Activator of Telomere-Bound Telomerase , 2002, Science.

[21]  G. Carman,et al.  Phosphorylation of the Yeast Phospholipid Synthesis Regulatory Protein Opi1p by Protein Kinase A* , 2001, Journal of Biological Chemistry.

[22]  Gene Ontology Consortium The Gene Ontology (GO) database and informatics resource , 2003 .

[23]  D. Goldberg,et al.  Assessing experimentally derived interactions in a small world , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Hanno Steen,et al.  Development of human protein reference database as an initial platform for approaching systems biology in humans. , 2003, Genome research.

[25]  Martin Kupiec,et al.  A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Thomas Kodadek,et al.  Physical and functional association of RNA polymerase II and the proteasome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Thomas J. Begley,et al.  Global network analysis of phenotypic effects: Protein networks and toxicity modulation in Saccharomyces cerevisiae , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  G. Cagney,et al.  Proteasome involvement in the repair of DNA double-strand breaks. , 2004, Molecular cell.

[29]  H. Lehrach,et al.  A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. , 2004, Molecular cell.

[30]  Kara Dolinski,et al.  Saccharomyces Genome Database (SGD) provides tools to identify and analyze sequences from Saccharomyces cerevisiae and related sequences from other organisms , 2004, Nucleic Acids Res..

[31]  K. Chao,et al.  Steiner Minimal Trees , 2005 .

[32]  John D. Storey,et al.  A network-based analysis of systemic inflammation in humans , 2005, Nature.

[33]  T. de Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres. , 2005, Genes & development.

[34]  Alex Zelikovsky,et al.  Tighter Bounds for Graph Steiner Tree Approximation , 2005, SIAM J. Discret. Math..

[35]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[36]  R. Karp,et al.  From the Cover : Conserved patterns of protein interaction in multiple species , 2005 .

[37]  Michelle S. Scott,et al.  Identifying Regulatory Subnetworks for a Set of Genes* , 2005, Molecular & Cellular Proteomics.

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

[39]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[40]  M. Longhese,et al.  Telomeres and DNA damage checkpoints. , 2005, Biochimie.

[41]  A. Barabasi,et al.  A Protein–Protein Interaction Network for Human Inherited Ataxias and Disorders of Purkinje Cell Degeneration , 2006, Cell.

[42]  K. Friedman,et al.  Proteasome-dependent degradation of Est1p regulates the cell cycle–restricted assembly of telomerase in Saccharomyces cerevisiae , 2006, Nature Structural &Molecular Biology.

[43]  D. Shore,et al.  The KEOPS Complex: A Rosetta Stone for Telomere Regulation? , 2006, Cell.

[44]  T. Ideker,et al.  Supporting Online Material for A Systems Approach to Mapping DNA Damage Response Pathways , 2006 .

[45]  J. Workman,et al.  RSC exploits histone acetylation to abrogate the nucleosomal block to RNA polymerase II elongation. , 2006, Molecular cell.

[46]  Alex Zelikovsky,et al.  A series of approximation algorithms for the acyclic directed steiner tree problem , 1997, Algorithmica.

[47]  T. Ideker,et al.  Comprehensive curation and analysis of global interaction networks in Saccharomyces cerevisiae , 2006, Journal of biology.

[48]  Leonid Kruglyak,et al.  Telomere Length as a Quantitative Trait: Genome-Wide Survey and Genetic Mapping of Telomere Length-Control Genes in Yeast , 2006, PLoS genetics.

[49]  Eytan Ruppin,et al.  Inferring Functional Pathways from Multi-Perturbation Data , 2006, ISMB.

[50]  B. Cairns,et al.  The RSC Chromatin Remodeling Complex Bears an Essential Fungal-Specific Protein Module With Broad Functional Roles , 2006, Genetics.

[51]  M. Foiani,et al.  The Rad53 signal transduction pathway: Replication fork stabilization, DNA repair, and adaptation. , 2006, Experimental cell research.

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

[53]  David Lydall,et al.  A Genome-Wide Screen Identifies the Evolutionarily Conserved KEOPS Complex as a Telomere Regulator , 2006, Cell.

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

[55]  R. Rothstein,et al.  The Slx5-Slx8 Complex Affects Sumoylation of DNA Repair Proteins and Negatively Regulates Recombination , 2007, Molecular and Cellular Biology.

[56]  Sharad Kumar,et al.  Caspase function in programmed cell death , 2007, Cell Death and Differentiation.

[57]  M. Moran,et al.  Large-scale mapping of human protein–protein interactions by mass spectrometry , 2007, Molecular systems biology.

[58]  K. Gunsalus,et al.  Network modeling links breast cancer susceptibility and centrosome dysfunction. , 2007, Nature genetics.

[59]  Mary B. Kroetz,et al.  The Yeast Hex3·Slx8 Heterodimer Is a Ubiquitin Ligase Stimulated by Substrate Sumoylation* , 2007, Journal of Biological Chemistry.

[60]  R. Verdun,et al.  Replication and protection of telomeres , 2007, Nature.

[61]  Yigong Shi,et al.  Apoptosome: a platform for the activation of initiator caspases , 2007, Cell Death and Differentiation.

[62]  T. Ideker,et al.  Network-based classification of breast cancer metastasis , 2007, Molecular systems biology.

[63]  Rebecca C Taylor,et al.  Apoptosis: controlled demolition at the cellular level , 2008, Nature Reviews Molecular Cell Biology.

[64]  A. Strasser,et al.  The BCL-2 protein family: opposing activities that mediate cell death , 2008, Nature Reviews Molecular Cell Biology.

[65]  R. Sharan,et al.  A systems-level approach to mapping the telomere length maintenance gene circuitry , 2008, Molecular systems biology.

[66]  T. Cech,et al.  Multiple Yeast Genes, Including Paf1 Complex Genes, Affect Telomere Length via Telomerase RNA Abundance , 2008, Molecular and Cellular Biology.