PT  - JOURNAL ARTICLE
AU  - Taylor P. Enrico
AU  - Wayne Stallaert
AU  - Elizaveta T. Wick
AU  - Peter Ngoi
AU  - Seth M. Rubin
AU  - Nicholas G. Brown
AU  - Jeremy E. Purvis
AU  - Michael J. Emanuele
TI  - Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
AID  - 10.1101/2021.04.23.441013
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.23.441013
4099  - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441013.short
4100  - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441013.full
AB  - 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 StatementThe authors have declared no competing interest.