Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer

Natasha S. Latysheva, Matt E. Oates, Louis Maddox, Tilman Flock, Julian Gough, Marija Buljan, Robert J. Weatheritt, M. Madan Babu

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)
265 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)579-592
Number of pages14
JournalMolecular Cell
Volume63
Issue number4
DOIs
Publication statusPublished - 18 Aug 2016

Keywords

  • gene fusion
  • fusion protein
  • cancer genomics
  • protein interaction networks

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