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

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 Fplays a key role in the CDK-RB network and raises the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.

Coordinating gene expression during the cell cycle

“…Cyclin E:CDK2 mediates hyperphosphorylation of RB and p130 and the complete inactivation of the DREAM complex (Figure 3, late G1/early S). Hyperphosphorylated forms of RB and p130 do not interact with E2Fs or MuvB, and p130 is degraded upon ubiquitination by SCF:SKP2 and SCF:cyclin F complexes [78][79][80]. Furthermore, B-MYB, a component of the MMB:FOXM1 complex, is encoded by a G1/S cell cycle gene and its high expression promotes DREAM complex dissociation [81].…”

Proteomic Analysis Reveals a PLK1-Dependent G2/M Degradation Program and Links PKA-AKAP2 to Cell Cycle Control

“…Although the need for phosphorylation of some substrates has been suggested (D'Angiolella et al 2012), Cyclin F is unique in that it does not directly recognize phospho-degrons. This is illustrated by the fact that Cyclin F substrates can be ubiquitinated in vitro without the need for phosphorylation (Enrico et al 2021). Although we have not elucidated the full mechanism, our data suggest that PLK1 regulates Cyclin F-dependent degradation at the ligase-level by promoting the stability of the Cyclin F protein, rather than through control of each individual substrate.…”

“…Interestingly, unlike in the case of βTrCP, Cyclin F does not directly recognize phospho-degrons in substrates (Enrico et al, 2021). This raises the question as to how PLK1 promotes the degradation of Cyclin F substrates.…”

“…The DepMap uses CRISPR/Cas9 loss-of-function screens to provide a fitness score for each gene based on their impact on cell proliferation/viability. Importantly, genes whose fitness scores are highly correlated with each other are often physically or genetically linked to one another and may function within the same pathways (Hart et al 2015;Enrico et al 2021). PDCD10, the strongest AKAP2 interactor, is highly correlated with multiple genes functioning within the Hippo tumor suppressor network (Figure 6E).…”