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

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

doi:10.1016/j.molcel.2016.07.008

Cited by 66 publications

(49 citation statements)

References 57 publications

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“…Therefore, ChiPPI uncovers that parental genes in fusions are hubs in biological networks prior to the fusion event, as has also been suggested in a recent study by Latysheva et al. (32). Consequently, fusions reduce the radius of the protein interaction networks by connecting previously non-connected parts and reduce the network betweenness centrality.…”

Section: Resultsmentioning

confidence: 99%

ChiPPI: a novel method for mapping chimeric protein–protein interactions uncovers selection principles of protein fusion events in cancer

Frenkel‐Morgenstern

Gorohovski

Tagore

et al. 2017

Nucleic Acids Research

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Fusion proteins, comprising peptides deriving from the translation of two parental genes, are produced in cancer by chromosomal aberrations. The expressed fusion protein incorporates domains of both parental proteins. Using a methodology that treats discrete protein domains as binding sites for specific domains of interacting proteins, we have cataloged the protein interaction networks for 11 528 cancer fusions (ChiTaRS-3.1). Here, we present our novel method, chimeric protein–protein interactions (ChiPPI) that uses the domain–domain co-occurrence scores in order to identify preserved interactors of chimeric proteins. Mapping the influence of fusion proteins on cell metabolism and pathways reveals that ChiPPI networks often lose tumor suppressor proteins and gain oncoproteins. Furthermore, fusions often induce novel connections between non-interactors skewing interaction networks and signaling pathways. We compared fusion protein PPI networks in leukemia/lymphoma, sarcoma and solid tumors finding distinct enrichment patterns for each disease type. While certain pathways are enriched in all three diseases (Wnt, Notch and TGF β), there are distinct patterns for leukemia (EGFR signaling, DNA replication and CCKR signaling), for sarcoma (p53 pathway and CCKR signaling) and solid tumors (FGFR and EGFR signaling). Thus, the ChiPPI method represents a comprehensive tool for studying the anomaly of skewed cellular networks produced by fusion proteins in cancer.

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Section: Resultsmentioning

confidence: 99%

ChiPPI: a novel method for mapping chimeric protein–protein interactions uncovers selection principles of protein fusion events in cancer

Frenkel‐Morgenstern

Gorohovski

Tagore

et al. 2017

Nucleic Acids Research

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“…Many malignancies bear fusion-protein translocations involving portions of TFs (Bradner et al, 2017; Kim et al, 2017; Latysheva et al, 2016). These abnormal gene products often fuse a DNA-or chromatin-binding domain to a wide array of partners, many of which are IDRs.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Boija

Klein

Sabari

et al. 2018

Cell

1,450

1,301

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Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well-characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

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“…For example, the LCD of FUS, which is involved in SG targeting and aggregation in ALS, has been shown to undergo oncogenic fusion events in liposarcomas [118]. Indeed, cancer-related fusion proteins are often enriched in disordered low-complexity domains, indicating this may be a common mechanism [119,120]. Indeed, the transcriptional activation potential of FUS LCD, as well as its human homologs EWSR1 and TAF15, implicated together in a family of cancers, is highly correlated with their in vitro hydrogel binding capability and ability to recruit the C-terminal domain of polymerase II to such hydrogels [90].…”

Section: Disease Pathology and Agingmentioning

confidence: 99%

Protein Phase Separation: A New Phase in Cell Biology

Boeynaems

Alberti

Fawzi

et al. 2018

Trends in Cell Biology

1,711

1,517

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Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

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

Cited by 66 publications

References 57 publications

ChiPPI: a novel method for mapping chimeric protein–protein interactions uncovers selection principles of protein fusion events in cancer

ChiPPI: a novel method for mapping chimeric protein–protein interactions uncovers selection principles of protein fusion events in cancer

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Protein Phase Separation: A New Phase in Cell Biology

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