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

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. [Display omitted] •Cyclin F targets activating E2Fs for proteasomal degradation during late S and in G2•Cyclin F controls one of the main transcriptional engines of the cell cycle•Degradation of activator E2Fs resets the system and prevents premature S-phase entry•Long-term stabilization of activator E2Fs induces DNA damage and impairs cell fitness Clijsters et al. elucidate how cyclin F controls a major transcriptional cell-cycle engine. The authors show that activating E2Fs are targeted for proteasomal degradation in late S and G2, resetting the transcriptional program and preventing unscheduled entry into the next S phase. Long-term stabilization of activator E2Fs impairs cell fitness.