Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

Abstract

E2F7 and E2F8 act as tumor suppressors via transcriptional repression of genes involved in S‐phase entry and progression. Previously, we demonstrated that these atypical E2Fs are degraded by APC/CCdh1 during G1 phase of the cell cycle. However, the mechanism driving the downregulation of atypical E2Fs during G2 phase is unknown. Here, we show that E2F7 is targeted for degradation by the E3 ubiquitin ligase SCFcyclin F during G2. Cyclin F binds via its cyclin domain to a conserved C‐terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin F nor the CY motifs in the C‐terminus of E2F8, implying a different regulatory mechanism than for E2F7. Importantly, depletion of cyclin F causes an atypical‐E2F‐dependent delay of the G2/M transition, accompanied by reduced expression of E2F target genes involved in DNA repair. Live cell imaging of DNA damage revealed that cyclin F‐dependent regulation of atypical E2Fs is critical for efficient DNA repair and cell cycle progression.

E2F transcription regulation: an orphan cyclin enters the stage

“…The timely degradation of E2Fs via cyclin F helps to finally answer the long-standing question on how the activity of E2F activators, after peaking in G1 and S phases, drastically declines once cells progress through G2 (Clijsters et al, 2019) (Fig 1A). The importance of cyclin F in regulating E2Fs is further unraveled in the study by Yuan et al (2019), which shows that cyclin F is also responsible for timely degradation of the atypical repressor E2F7. Given the overlap of DNA binding sites, the finding that two types of E2Fs, activators and the atypical repressor E2F7, are under the control of the same E3 ligase seems surprising at first sight.…”

“…A series of recent investigations, including two studies in The EMBO Journal, has now unraveled extensive links between cyclin F activity and transcriptional regulation through degradation of the transcriptional activators E2F1, E2F2, and E2F3a (Burdova et al, 2019;Clijsters et al, 2019), as well as the atypical repressor E2F7 (Yuan et al, 2019). Furthermore, it is clear that unscheduled E2F activity resulting from absence of cyclin F leads to a marked disturbance in cell cycle progression and increase in DNA damage (Clijsters et al, 2019;Yuan et al, 2019). Furthermore, it is clear that unscheduled E2F activity resulting from absence of cyclin F leads to a marked disturbance in cell cycle progression and increase in DNA damage (Clijsters et al, 2019;Yuan et al, 2019).…”

“…for CDC6, EXO1, RRM2, or SLPB. In addition, cyclin F has now also been shown to regulate DNA damage response genes responsible for base excision repair, nucleotide excision repair, DNA mismatch repair, and homologous recombination, which were previously weakly linked to cyclin F on the substrate level (Yuan et al, 2019). With the additional loss of control over timely degradation of E2F transcription factors, the absence of cyclin F results in over-licensing and mitotic transcription (Clijsters et al, 2019).…”

“…Cyclin F was previously implicated in transcriptional regulation mainly by control of the phosphorylation status of B-Myb (Klein et al, 2015). A series of recent investigations, including two studies in The EMBO Journal, has now unraveled extensive links between cyclin F activity and transcriptional regulation through degradation of the transcriptional activators E2F1, E2F2, and E2F3a (Burdova et al, 2019;Clijsters et al, 2019), as well as the atypical repressor E2F7 (Yuan et al, 2019). Thereby, cyclin F emerges as a key factor in ensuring the orderly initiation, execution, and termination of precisely one round of replication at several levels.…”

“…Thereby, cyclin F emerges as a key factor in ensuring the orderly initiation, execution, and termination of precisely one round of replication at several levels. Furthermore, it is clear that unscheduled E2F activity resulting from absence of cyclin F leads to a marked disturbance in cell cycle progression and increase in DNA damage (Clijsters et al, 2019;Yuan et al, 2019).…”