General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: Graphical Abstract Highlights d Parents of fusion proteins occupy central positions in protein interaction networks d Parents are rich in interaction-mediating features, which are often lost via fusion d Fusions preferentially join proteins with no previous connection in protein networks d Fusion proteins escape

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... egulation by losing posttranslational modification sites SUMMARY 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.