title: Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer.
abstract: Gene fusions are common cancer-causing mutations, but the molecular principles by which fusion protein products affect interaction networks and cause disease are not well understood. Here, we perform an integrative analysis of the structural, interactomic, and regulatory properties of thousands of putative fusion proteins. We demonstrate that genes that form fusions (i.e., parent genes) tend to be highly connected hub genes, whose protein products are enriched in structured and disordered interaction-mediating features. Fusion often results in the loss of these parental features and the depletion of regulatory sites such as post-translational modifications. Fusion products disproportionately connect proteins that did not previously interact in the protein interaction network. In this manner, fusion products can escape cellular regulation and constitutively rewire protein interaction networks. We suggest that the deregulation of central, interaction-prone proteins may represent a widespread mechanism by which fusion proteins alter the topology of cellular signaling pathways and promote cancer.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: natashal@mrc-lmb.cam.ac.uk.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Latysheva
authors.affiliation: Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Matt E
authors.initials: ME
authors.lastname: Oates
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Maddox
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Tilman
authors.initials: T
authors.lastname: Flock
authors.affiliation: Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Gough
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Marija
authors.initials: M
authors.lastname: Buljan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weatheritt
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: madanm@mrc-lmb.cam.ac.uk.
authors.forename: M Madan
authors.initials: MM
authors.lastname: Babu
mesh_terms: D019295:Computational Biology; D030562:Databases, Protein; D050939:Gene Fusion; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D009363:Neoplasm Proteins; D014157:Transcription Factors
keywords: cancer genomics; fusion protein; gene fusion; protein interaction networks