Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset

Yuan, Xiutang; Srividhya, Jeyaraman; Luca, Thomas De; Lee, Ju-hyong E.; Pomerening, Joseph R.

doi:10.1091/mbc.e13-08-0480

Cited by 36 publications

(37 citation statements)

References 39 publications

(38 reference statements)

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“…Depletion of either protein had no detectable effect on the abundance of the other, suggesting post-translational regulation of their ability to control each other during mitosis. Cdh1 depletion accelerated S-phase entry, in agreement with previous reports, (Figure 6B) (García-Higuera et al, 2008; Sigl et al, 2009; Yuan et al, 2014). Forty-one percent of control cells were incorporating EdU at six hours after nocodazole release, whereas seventy-seven percent of Cdh1 depleted cells had entered S-phase at the same time point.…”

Section: Resultssupporting

confidence: 93%

“…Cdh1 overexpression in G1 cells prevents S-phase entry, whereas Cdh1 depletion or genetic inactivation accelerates G1 progression (Sigl et al, 2009; Sørensen et al, 2001; Yuan et al, 2014). The role of APC/C in restricting S-phase entry is conserved in budding and fission yeast, flies, worms, chickens, mice, and humans (Fay et al, 2002; García-Higuera et al, 2008; Kitamura et al, 1998; Sigrist and Lehner, 1997; Sudo et al, 2001; Wirth et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

et al. 2016

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SUMMARY The Anaphase Promoting Complex/Cyclosome (APC/C) is an ubiquitin ligase and core component of the cell cycle oscillator. During G1-phase APC/C binds to its substrate receptor Cdh1 and APC/CCdh1 plays an important role in restricting S-phase entry and maintaining genome integrity. We describe a reciprocal feedback circuit between APC/C and a second ubiquitin ligase, the SCF (Skp1-Cul1-F box). We show that Cyclin F, a cell cycle regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCFCyclin F. Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. These data indicate that the coordinated, temporal ordering of Cyclin F and Cdh1 degradation, organized in a double-negative feedback loop, represents a fundamental aspect of cell cycle control. This mutual antagonism could be a feature of other oscillating systems.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

et al. 2016

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“…However, rapid cell cycle entry can ultimately reduce proliferation by causing damage during DNA replication. Notably, cells lacking Cdh1 rapidly progress through G1 phase (Choudhury et al, 2016; Sigl et al, 2009; Yuan et al, 2014) and accumulate DNA damage, based on staining for the damage marker γH2AX, and consistent with prior reports (Supplemental Figure 5B) (Bassermann et al, 2008; Choudhury et al, 2016; Engelbert et al, 2008; Sigl et al, 2009). We therefore tested the effect of longer-term expression of the various mutant versions of Cyclin F in HCT116 cells.…”

Section: Resultssupporting

confidence: 89%

The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

et al. 2017

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SUMMARY The oncogenic AKT kinase is a key regulator of apoptosis, cell growth and cell cycle progression. Despite its important role in proliferation, it remains largely unknown how AKT is mechanistically linked to cell cycle. We show here that Cyclin F, a substrate receptor F-box protein for the SCF family of E3 ubiquitin ligases, is a bona fide AKT substrate. Cyclin F expression oscillates throughout the cell cycle, a rare feature among the 69 human F-box proteins, and all of its known substrates are involved in proliferation. AKT phosphorylation of Cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. Importantly, expression of mutant versions of Cyclin F that cannot be phosphorylated by AKT impair cell cycle entry. Our data suggest that Cyclin F transmits mitogen signaling through AKT to the core cell cycle machinery. This discovery has potential implications for proliferative control in malignancies where AKT is activated.

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“…37,38 Finally, a recent report argued that cyclin E is mainly responsible for premature S-phase entry upon Cdh1 depletion. 39 Mitotic entry with incompletely replicated DNA can lead to DNA double-strand breaks during chromosome condensation and separation, which is consistent with our finding of an increase in γH2AX foci. Moreover, replication intermediates may lead to mitotic aberrations.…”

Section: Discussionsupporting

confidence: 92%

The role of APC/CCdh1 in replication stress and origin of genomic instability

et al. 2015

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It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

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Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset

Cited by 36 publications

References 39 publications

APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

The role of APC/CCdh1 in replication stress and origin of genomic instability

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