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

Cell cycle gene expression programs fuel proliferation and are universally
dysregulated in cancer. The retinoblastoma (RB)-family of proteins, RB1,
RBL1/p107, and RBL2/p130, coordinately represses cell cycle gene
expression, inhibiting proliferation, and suppressing tumorigenesis.
Phosphorylation of RB-family proteins by cyclin-dependent kinases is
firmly established. Like phosphorylation, ubiquitination 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 CRISPR/Cas9 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 mutant
version of p130, which cannot be ubiquitinated, severely impaired
proliferative capacity and cell cycle progression. Consistently, we
observed reduced expression of cell cycle gene transcripts, as well a
reduced abundance of cell cycle proteins, analyzed by quantitative,
iterative immunofluorescent imaging. These data suggest a key role for
SCFcyclin F in the CDK-RB network and raise the possibility that aberrant
p130 degradation could dysregulate the cell cycle in human cancers.