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Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2

Taylor P. Enrico, Wayne Stallaert, Elizaveta T. Wick, Peter Ngoi, Seth M. Rubin, Nicholas G. Brown, Jeremy E. Purvis, Michael J. Emanuele
doi: https://doi.org/10.1101/2021.04.23.441013
Taylor P. Enrico
1Department of Pharmacology. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
2Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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Wayne Stallaert
3Department of Genetics. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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Elizaveta T. Wick
1Department of Pharmacology. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
2Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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Peter Ngoi
4Department of Chemistry and Biochemistry. University of California at Santa Cruz, Santa Cruz, CA, USA
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Seth M. Rubin
4Department of Chemistry and Biochemistry. University of California at Santa Cruz, Santa Cruz, CA, USA
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Nicholas G. Brown
1Department of Pharmacology. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
2Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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Jeremy E. Purvis
2Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
3Department of Genetics. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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Michael J. Emanuele
1Department of Pharmacology. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
2Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, USA.
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  • For correspondence: emanuele@email.unc.edu
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Abstract

Cell cycle gene expression programs fuel proliferation and are dysregulated in many cancers. The retinoblastoma-family proteins, RB, p130/RBL2 and p107/RBL1, coordinately repress cell cycle gene expression, inhibiting proliferation and suppressing tumorigenesis. Ubiquitin-dependent protein degradation is essential to cell cycle control, and numerous proliferative regulators, tumor suppressors, and oncoproteins are ubiquitinated. However, little is known about the role of ubiquitin signaling in controlling RB-family proteins. A systems genetics analysis of several hundred CRISPR/Cas9 loss-of-function screens suggested the potential regulation of the RB-network by cyclin F, a substrate recognition receptor for the SCF family of E3 ligases. We demonstrate that RBL2/p130 is a direct substrate of SCFcyclin F. We map a cyclin F regulatory site to a flexible linker in the p130 pocket domain, and show that this site mediates binding, stability, and ubiquitination. Expression of a non-degradable p130 represses cell cycle gene expression and strongly reduces proliferation. These data suggest that SCFcyclin F plays a key role in the CDK-RB network and raises the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.

Competing Interest Statement

The authors have declared no competing interest.

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Posted April 24, 2021.
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Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Taylor P. Enrico, Wayne Stallaert, Elizaveta T. Wick, Peter Ngoi, Seth M. Rubin, Nicholas G. Brown, Jeremy E. Purvis, Michael J. Emanuele
bioRxiv 2021.04.23.441013; doi: https://doi.org/10.1101/2021.04.23.441013
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Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Taylor P. Enrico, Wayne Stallaert, Elizaveta T. Wick, Peter Ngoi, Seth M. Rubin, Nicholas G. Brown, Jeremy E. Purvis, Michael J. Emanuele
bioRxiv 2021.04.23.441013; doi: https://doi.org/10.1101/2021.04.23.441013

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