Defining the condensate landscape of fusion oncoproteins.

Autor: Tripathi S; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Shirnekhi HK; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Gorman SD; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Arrakis Therapeutics, 830 Winter St, Waltham, MA, 02451, USA., Chandra B; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Baggett DW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Park CG; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Somjee R; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Rhodes College, Memphis, TN, USA.; Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA., Lang B; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Center of Excellence for Data-Driven Discovery, Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Hosseini SMH; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Center of Excellence for Data-Driven Discovery, Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Pioso BJ; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Li Y; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA., Iacobucci I; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Gao Q; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Edmonson MN; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Rice SV; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhou X; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Bollinger J; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mitrea DM; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Dewpoint Therapeutics, 451 D Street, Suite 104, Boston, MA, 02210, USA., White MR; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; IDEXX Laboratories, Inc., One IDEXX Drive, Westbrook, ME, 04092, USA., McGrail DJ; Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Jarosz DF; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA., Yi SS; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.; Department of Biomedical Engineering, and Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA., Babu MM; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Center of Excellence for Data-Driven Discovery, Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mullighan CG; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Sahni N; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA., Kriwacki RW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. richard.kriwacki@stjude.org.; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN, USA. richard.kriwacki@stjude.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Sep 28; Vol. 14 (1), pp. 6008. Date of Electronic Publication: 2023 Sep 28.
DOI: 10.1038/s41467-023-41655-2
Abstrakt: Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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