Dataset Information

Cell cycle oscillators underlying orderly proteolysis of E2F8.

ABSTRACT: E2F8 is a transcriptional repressor that antagonizes E2F1 at the crossroads of the cell cycle, apoptosis, and cancer. Previously, we discovered that E2F8 is a direct target of the APC/C ubiquitin ligase. Nevertheless, it remains unknown how E2F8 is dynamically controlled throughout the entirety of the cell cycle. Here, using newly developed human cell-free systems that recapitulate distinct inter-mitotic and G1 phases and a continuous transition from prometaphase to G1, we reveal an interlocking dephosphorylation switch coordinating E2F8 degradation with mitotic exit and the activation of APC/C^Cdh1. Further, we uncover differential proteolysis rates for E2F8 at different points within G1 phase, accounting for its accumulation in late G1 while APC/C^Cdh1 is still active. Finally, we demonstrate that the F-box protein Cyclin F regulates E2F8 in G2-phase. Altogether, our data define E2F8 regulation throughout the cell cycle, illuminating an extensive coordination between phosphorylation, ubiquitination and transcription in mammalian cell cycle.

SUBMITTER: Wasserman D

PROVIDER: S-EPMC7185961 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cell cycle oscillators underlying orderly proteolysis of E2F8.

Wasserman Danit D Nachum Sapir S Cohen Meital M Enrico Taylor P TP Noach-Hirsh Meirav M Parasol Jasmin J Zomer-Polak Sarit S Auerbach Naomi N Sheinberger-Chorni Evelin E Nevenzal Hadas H Levi-Dadon Nofar N Wang Xianxi X Lahmi Roxane R Michaely Efrat E Gerber Doron D Emanuele Michael J MJ Tzur Amit A

Molecular biology of the cell 20200129 8

E2F8 is a transcriptional repressor that antagonizes E2F1 at the crossroads of the cell cycle, apoptosis, and cancer. Previously, we discovered that E2F8 is a direct target of the APC/C ubiquitin ligase. Nevertheless, it remains unknown how E2F8 is dynamically controlled throughout the entirety of the cell cycle. Here, using newly developed human cell-free systems that recapitulate distinct inter-mitotic and G1 phases and a continuous transition from prometaphase to G1, we reveal an interlocking ...[more]

PMID: 31995441

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Project description:BackgroundThe biochemical oscillator that controls periodic events during the Xenopus embryonic cell cycle is centered on the activity of CDKs, and the cell cycle is driven by a protein circuit that is centered on the cyclin-dependent protein kinase CDK1 and the anaphase-promoting complex (APC). Many studies have been conducted to confirm that the interactions in the cell cycle can produce oscillations and predict behaviors such as synchronization, but much less is known about how the various elaborations and collective behavior of the basic oscillators can affect the robustness of the system. Therefore, in this study, we investigate and model a multi-cell system of the Xenopus embryonic cell cycle oscillators that are coupled through a common complex protein, and then analyze their synchronization ability under four different external stimuli, including a constant input signal, a square-wave periodic signal, a sinusoidal signal and a noise signal.ResultsThrough bifurcation analysis and numerical simulations, we obtain synchronization intervals of the sensitive parameters in the individual oscillator and the coupling parameters in the coupled oscillators. Then, we analyze the effects of these parameters on the synchronization period and amplitude, and find interesting phenomena, e.g., there are two synchronization intervals with activation coefficient in the Hill function of the activated CDK1 that activates the Plk1, and different synchronization intervals have distinct influences on the synchronization period and amplitude. To quantify the speediness and robustness of the synchronization, we use two quantities, the synchronization time and the robustness index, to evaluate the synchronization ability. More interestingly, we find that the coupled system has an optimal signal strength that maximizes the synchronization index under different external stimuli. Simulation results also show that the ability and robustness of the synchronization for the square-wave periodic signal of cyclin synthesis is strongest in comparison to the other three different signals.ConclusionsThese results suggest that the reaction process in which the activated cyclin-CDK1 activates the Plk1 has a very important influence on the synchronization ability of the coupled system, and the square-wave periodic signal of cyclin synthesis is more conducive to the synchronization and robustness of the coupled cell-cycle oscillators. Our study provides insight into the internal mechanisms of the cell cycle system and helps to generate hypotheses for further research.

Dataset Information

Cell cycle oscillators underlying orderly proteolysis of E2F8.

Publications

Cell cycle oscillators underlying orderly proteolysis of E2F8.

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