FBXO46

FBXO46 is an F-box protein that serves as the substrate-recognition subunit of an SCF E3 ubiquitin ligase complex (SCF^FBXO46), coupling its activity to cell cycle progression, senescence control, and the DNA-damage response (PMID:30171069, PMID:39548735). Under unstressed conditions it recognizes an RXXR motif at the C-terminus of FBXO31 to direct FBXO31 polyubiquitination and proteasomal degradation, holding FBXO31 at basal levels and thereby preventing premature cellular senescence (PMID:30171069). FBXO46 also directly binds Mdm2 and blocks its auto-ubiquitination, stabilizing Mdm2 so that it can ubiquitinate and degrade p53, which enhances proliferation and G1/S progression (PMID:39548735). Following DNA damage, ATM kinase phosphorylates FBXO46 at Ser-21 and Ser-67, triggering FBXO46 degradation through FBXO31 in a negative-feedback loop that relieves FBXO31 degradation and permits FBXO31 accumulation for genomic stability (PMID:30171069).

1. 2018 High

   Established FBXO46 as a functional SCF substrate-recognition subunit and identified its first substrate, defining how basal FBXO31 levels are set to restrain senescence.

   Evidence Molecular docking, RXXR-motif mutagenesis, co-IP, ubiquitination assays, and FBXO46 depletion with senescence readout in cells

   PMID:30171069

   Open questions at the time

   • Full SCF complex composition (Skp1/Cul1/Rbx1 with FBXO46) not enumerated in the finding
   • No structural model of the FBXO46–FBXO31 interface beyond docking
   • Physiological contexts in which FBXO31-driven senescence is engaged not mapped
2. 2018 High

   Resolved how the DNA-damage response reverses FBXO46 activity, showing ATM phosphorylation converts FBXO46 into a degradation substrate to create a self-limiting feedback loop.

   Evidence Phosphorylation-site mapping, ATM inhibitor/activator experiments, phospho-site mutagenesis, and degradation/ubiquitination assays

   PMID:30171069

   Open questions at the time

   • Whether ATM phosphorylation acts as a degron recognized by FBXO31 directly is not detailed
   • Quantitative kinetics of the feedback loop after damage not established
   • Other kinases or DNA-damage inputs converging on FBXO46 not tested
3. 2024 Medium

   Extended FBXO46 function beyond substrate degradation to substrate stabilization, showing it protects Mdm2 to suppress p53 and drive proliferation.

   Evidence Co-IP for direct binding, Mdm2 auto-ubiquitination inhibition assays, p53 degradation assays, and cell proliferation/cycle analysis upon FBXO46 manipulation

   PMID:39548735

   Open questions at the time

   • No mutagenesis or structural validation of the FBXO46–Mdm2 interaction reported
   • Whether Mdm2 stabilization requires the SCF complex or is an F-box-independent activity is unclear
   • Single-lab finding without reciprocal or in vivo confirmation

• How FBXO46's two opposing activities—SCF-mediated FBXO31 degradation versus Mdm2 stabilization—are integrated within the same cell and which dominates in a given physiological or stress state remains unresolved.
• No study reconciles the senescence/genomic-stability axis with the Mdm2–p53 proliferation axis
• Broader substrate repertoire of SCF^FBXO46 unknown
• In vivo and disease relevance not established