The SCF^FBXO46 ubiquitin ligase complex mediates degradation of the tumor suppressor FBXO31 and thereby prevents premature cellular senescence.

The tumor suppressor F-box protein 31 (FBXO31) is indispensable for maintaining genomic stability. Its levels drastically increase following DNA damage, leading to cyclin D1 and MDM2 degradation and G₁ and G₂/M arrest. Prolonged arrest in these phases leads to cellular senescence. Accordingly, FBXO31 needs to be kept at low basal levels in unstressed conditions for normal cell cycle progression during growth and development. However, the molecular mechanism maintaining these basal FBXO31 levels has remained unclear. Here, we identified the F-box family SCF-E3 ubiquitin ligase FBXO46 (SCF^FBXO46) as an important proteasomal regulator of FBXO31 and found that FBXO46 helps maintain basal FBXO31 levels under unstressed conditions and thereby prevents premature senescence. Using molecular docking and mutational studies, we showed that FBXO46 recognizes an RXXR motif located at the FBXO31 C terminus to direct its polyubiquitination and thereby proteasomal degradation. Furthermore, FBXO46 depletion enhanced the basal levels of FBXO31, resulting in senescence induction. In response to genotoxic stress, ATM (ataxia telangiectasia-mutated) Ser/Thr kinase-mediated phosphorylation of FBXO31 at Ser-278 maintained FBXO31 levels. In contrast, activated ATM phosphorylated FBXO46 at Ser-21/Ser-67, leading to its degradation via FBXO31. Thus, ATM-catalyzed phosphorylation after DNA damage governs FBXO31 levels and FBXO46 degradation via a negative feedback loop. Collectively, our findings reveal that FBXO46 is a crucial proteasomal regulator of FBXO31 and thereby prevents senescence in normal growth conditions. They further indicate that FBXO46-mediated regulation of FBXO31 is abrogated following genotoxic stress to promote increased FBXO31 levels for maintenance of genomic stability.

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