Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression. (2nd September 2019)

• Record Type: Journal Article
• Authors: Yuan, Ruixue; Liu, Qingwu; Segeren, Hendrika A; Yuniati, Laurensia; Guardavaccaro, Daniele; Lebbink, Robert J; Westendorp, Bart; de Bruin, Alain
• Is Part Of: EMBO journal. Volume 38:Number 20(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-09-02
• Subjects: cell cycle -- DNA damage -- E2F -- proteolysis -- SCF cyclin F; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018101430
• Languages: English
• ISSNs: 0261-4189

Abstract

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/C C dh1 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 SCF cyclin 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 SCF cyclin F remains stable during G2. Furthermore, SCF cyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCF cyclin 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. Synopsis: While degradation of atypical E2F7 and E2F8 transcriptional repressors during the G1 phase depends on APC/C‐Cdh1, the ubiquitin ligase SCF‐Cyclin F is now found to mediate their downregulation in G2 to ensure DNA repair gene expression and cell cycle progression. Cyclin F targets atypical E2Fs for proteasomal degradation during G2. Failure to degrade E2F7 causes DNA damage and delays G2/M progression. Cyclin F regulates expression of DNA replication and repair genes via atypical repressor E2Fs. Efficient DNA repair depends on Cyclin F‐mediated degradation of atypical E2Fs. Abstract : In addition to APC/C‐mediated proteolysis of atypical repressive E2Fs during G1, later downregulation via an SCF ubiquitin ligase is important for repair gene expression and G2/M transition.