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.
Highlights
The atypical E2Fs, E2F7 and E2F8, are transcriptional repressors controlling a network of genes that drive cell cycle progression
E2F7 and E2F8 are subjected to Cullin-RING ligase-dependent degradation during G2 and early M phase
We found that knockdown of cyclin F significantly reduced homologous recombination (HR) repair efficiency, and this repair deficiency was fully recovered by additional knockdown E2F7 and E2F8 (Figs 7A and EV5A; see Materials and Methods)
Summary
The atypical E2Fs, E2F7 and E2F8, are transcriptional repressors controlling a network of genes that drive cell cycle progression. Ectopic expression of atypical E2Fs leads to downregulation of these target genes accompanied by a permanent Sphase arrest and severe DNA damage (Westendorp et al, 2012; Yuan et al, 2018). In response to replication stress the repressor activity of atypical E2Fs is inhibited by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest (Yuan et al, 2018). These studies demonstrated that the proper regulation of atypical E2Fs during cell cycle progression and DNA damage is critical to avoid a detrimental effect on cell survival
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