Cyclin F Controls Cell-Cycle Transcriptional Outputs by Directing the Degradation of the Three Activator E2Fs

Mol Cell. 2019 Jun 20;74(6):1264-1277.e7. doi: 10.1016/j.molcel.2019.04.010. Epub 2019 May 23.


E2F1, E2F2, and E2F3A, the three activators of the E2F family of transcription factors, are key regulators of the G1/S transition, promoting transcription of hundreds of genes critical for cell-cycle progression. We found that during late S and in G2, the degradation of all three activator E2Fs is controlled by cyclin F, the substrate receptor of 1 of 69 human SCF ubiquitin ligase complexes. E2F1, E2F2, and E2F3A interact with the cyclin box of cyclin F via their conserved N-terminal cyclin binding motifs. In the short term, E2F mutants unable to bind cyclin F remain stable throughout the cell cycle, induce unscheduled transcription in G2 and mitosis, and promote faster entry into the next S phase. However, in the long term, they impair cell fitness. We propose that by restricting E2F activity to the S phase, cyclin F controls one of the main and most critical transcriptional engines of the cell cycle.

Keywords: E2F1; E2F2; E2F3A; F-box proteins; RNA-seq; SCF ligases; cell cycle; cyclin F; retinoblastoma; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics*
  • Cell Line, Tumor
  • Cyclins / genetics*
  • Cyclins / metabolism
  • E2F1 Transcription Factor / genetics*
  • E2F1 Transcription Factor / metabolism
  • E2F2 Transcription Factor / genetics*
  • E2F2 Transcription Factor / metabolism
  • E2F3 Transcription Factor / genetics*
  • E2F3 Transcription Factor / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Gene Expression Regulation
  • Genetic Fitness
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mutation
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Proteolysis
  • SKP Cullin F-Box Protein Ligases / genetics*
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction
  • Transcription, Genetic*
  • Ubiquitination


  • CCNF protein, human
  • Cyclins
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2F2 Transcription Factor
  • E2F2 protein, human
  • E2F3 Transcription Factor
  • SKP Cullin F-Box Protein Ligases