Defining the condensate landscape of fusion oncoproteins

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. W...

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Published in:Nature communications Vol. 14; no. 1; pp. 6008 - 25
Main Authors: Tripathi, Swarnendu, Shirnekhi, Hazheen K., Gorman, Scott D., Chandra, Bappaditya, Baggett, David W., Park, Cheon-Gil, Somjee, Ramiz, Lang, Benjamin, Hosseini, Seyed Mohammad Hadi, Pioso, Brittany J., Li, Yongsheng, Iacobucci, Ilaria, Gao, Qingsong, Edmonson, Michael N., Rice, Stephen V., Zhou, Xin, Bollinger, John, Mitrea, Diana M., White, Michael R., McGrail, Daniel J., Jarosz, Daniel F., Yi, S. Stephen, Babu, M. Madan, Mullighan, Charles G., Zhang, Jinghui, Sahni, Nidhi, Kriwacki, Richard W.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 28.09.2023
Nature Publishing Group
Nature Portfolio
Subjects:
13/106
14/19
631/114/663/2009
631/57/2269
Biomolecular Condensates
Carcinogenesis
Cell signaling
Cell Transformation, Neoplastic
Chromosome translocations
Condensates
Condensation
Cytoplasm
Functionals
Gene expression
HeLa Cells
Humanities and Social Sciences
Humans
Liquid phases
Localization
Machine learning
multidisciplinary
Oncogene Proteins, Fusion
Oncoproteins
Phase separation
Reagents
Science
Science (multidisciplinary)
Tumorigenesis
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Many fusion oncoproteins (FOs) form condensates, some form in the nucleus and regulate gene expression while others form in the cytoplasm and promote cell signaling. In this work, the authors report the analysis of physicochemical features to enable prediction of FO condensation behavior.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-41655-2