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

Clijsters, Linda; Hoencamp, Claire; Calis, Jorg J.A.; Marzio, Antonio; Handgraaf, Shanna M.; Cuitiño, Maria C.; Rosenberg, Brad R.; Leone, Gustavo; Pagano, Michele

doi:10.1016/j.molcel.2019.04.010

Cited by 72 publications

(63 citation statements)

References 60 publications

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“…While this could be also ascribed to technical issues related to the generation of CCNF K/O cell lines and the expression of E2F1 near to physiological levels, it is also possible to speculate that other cyclin F substrates could play an additive role in inducing DNA replication catastrophe. Interestingly, it has very recently been shown that cyclin F targets E2F1 and its paralogs E2F2 and E2F3 for degradation (Clijsters et al, 2019). While we have excluded E2F3 as a mediator of DNA replication catastrophe in CCNF K/O (Fig 4A and B), it is plausible that E2F2 accumulation could also play a role.…”

Section: Discussionmentioning

confidence: 81%

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E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

et al. 2019

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Cyclins are central engines of cell cycle progression in conjunction with cyclin‐dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F‐box domain an SCF (Skp1‐Cul1‐F‐box)‐type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F‐depleted cells. We find that SCF‐cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 81%

“…Interestingly, it has very recently been shown that cyclin F targets E2F1 and its paralogs E2F2 and E2F3 for degradation (Clijsters et al, 2019). The concomitant loss of cyclin F and Chk1 prompts uncontrolled E2F1 activity in the absence of checkpoint control inducing DNA replication catastrophe.…”

Section: Of 18mentioning

confidence: 99%

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

et al. 2019

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“…A recent study demonstrated that activator E2Fs (E2F1-3A) are also targeted by cyclin F for degradation during S and G2 phases (Clijsters et al, 2019). It raises a question whether the degradation of activator E2Fs and atypical E2Fs by cyclin F occurs simultaneously.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…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).…”

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confidence: 99%

“…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.…”

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confidence: 99%

E2F transcription regulation: an orphan cyclin enters the stage

Rösner

Sørensen

2019

The EMBO Journal

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Marked cyclin protein oscillations over the cell cycle ensure tight regulation of all cell cycle transitions. Despite expression patterns closely mirroring those of cyclin A, cyclin F has long been regarded as an odd outlier within the cyclin family. Constituting part of an E3 ubiquitin ligase, its main role was seen as highly restricted to timely degradation of very few key substrates to ensure termination of one error‐free round of replication. Now, a recent series of studies suggests that cyclin F has very similar roles as its closest relatives, merely mediated through a very different mechanism.

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

Cited by 72 publications

References 60 publications

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

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

E2F transcription regulation: an orphan cyclin enters the stage

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