F-box only protein 31 [FBX14] [FBX31] [PP2386]

PublicationsПравить

The SCF 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 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)


Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.

Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

MeSH Terms

  • Animals
  • Body Size
  • Evolution, Molecular
  • Gene Dosage
  • Genes, Tumor Suppressor
  • Humans
  • Longevity
  • Mathematical Concepts
  • Mice
  • Models, Genetic
  • Multigene Family
  • Mutation
  • Neoplasms
  • Risk Factors
  • Species Specificity

Keywords

  • Peto's paradox
  • Wright–Fisher model
  • algebraic model
  • cancer
  • evolution
  • tumour suppression