Редактирование: FBXO46 (раздел)

==Publications==

{{medline-entry
|title=The SCF  ubiquitin ligase complex mediates degradation of the tumor suppressor [[FBXO31]] and thereby prevents premature cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30171069
|abstract=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 G  and G /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 ) 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 R[i]XX[/i]R 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.
|mesh-terms=* Cellular Senescence
* F-Box Proteins
* Genomic Instability
* Humans
* Molecular Docking Simulation
* Phosphorylation
* Proteasome Endopeptidase Complex
* SKP Cullin F-Box Protein Ligases
* Tumor Suppressor Proteins
* Ubiquitination
|keywords=* ATM
* DNA damage
* E3 ubiquitin ligase
* F-box protein
* cell cycle
* flow cytometry
* post-transcriptional regulation
* post-translational modification (PTM)
* protein motif
* protein turnover
* senescence
* ubiquitin ligase
* ubiquitination
* ubiquitylation (ubiquitination)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200945
}}