Feedback regulation between atypical E2Fs and APC/C-Cdh1 coordinates cell cycle progression

Michiel Boekhout, Ruixue Yuan, Annelotte P. Wondergem, Hendrika A. Segeren, Elsbeth A. van Liere, Nesibu Awol, Imke Jansen, Rob M. F. Wolthuis, Alain de Bruin*, Bart Westendorp

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    14 Citations (Scopus)

    Abstract

    E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C-Cdc20. Importantly, atypical E2Fs can activate APC/C-Cdh1 by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C-Cdh1, which ensures balanced expression of cell cycle genes and normal cell cycle progression.

    Original languageEnglish
    Pages (from-to)414-427
    Number of pages14
    JournalEmbo Reports
    Volume17
    Issue number3
    DOIs
    Publication statusPublished - Mar-2016

    Keywords

    • anaphase-promoting complex
    • CDH1
    • cell cycle
    • DNA replication
    • E2F
    • UBIQUITIN CHAIN FORMATION
    • DNA-DAMAGE
    • S-PHASE
    • REPLICATION STRESS
    • MEDIATED DEGRADATION
    • ANAPHASE
    • CANCER
    • TRANSCRIPTION
    • GENES

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