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Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis

Wei Li, Jing Hu, Bi Shi, Francesco Palomba, Michelle A. Digman, Enrico Gratton, Hao Jiang
doi: https://doi.org/10.1101/536839
Wei Li
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
2Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
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Jing Hu
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
2Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
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Bi Shi
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
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Francesco Palomba
3Laboratory of Fluorescence Dynamics, The Henry Samueli School of Engineering, University of California, Irvine, CA, USA
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Michelle A. Digman
3Laboratory of Fluorescence Dynamics, The Henry Samueli School of Engineering, University of California, Irvine, CA, USA
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Enrico Gratton
3Laboratory of Fluorescence Dynamics, The Henry Samueli School of Engineering, University of California, Irvine, CA, USA
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Hao Jiang
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
2Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
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  • For correspondence: hj8d@virginia.edu
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ABSTRACT

It remains unknown if biophysical or material properties of biomolecular condensates regulate cancer. Here we show that AKAP95, a nuclear protein that regulates transcription and RNA splicing, plays an important role in tumorigenesis by supporting cancer cell growth and suppressing oncogene-induced senescence. AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and supporting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results link phase separation to tumorigenesis and uncover an important role of appropriate biophysical properties of protein condensates in gene regulation and cancer.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This revision has added experiments to show altered diffusion by the YF mutation, and added authors from UC Irvine, as well as re-reformatting of the paper.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 09, 2020.
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Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis
Wei Li, Jing Hu, Bi Shi, Francesco Palomba, Michelle A. Digman, Enrico Gratton, Hao Jiang
bioRxiv 536839; doi: https://doi.org/10.1101/536839
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Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis
Wei Li, Jing Hu, Bi Shi, Francesco Palomba, Michelle A. Digman, Enrico Gratton, Hao Jiang
bioRxiv 536839; doi: https://doi.org/10.1101/536839

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