SCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication

Walter, David; Hoffmann, Saskia; Komseli, Eirini Stavroula; Rappsilber, Juri; Gorgoulis, Vassilis G.; Sørensen, Claus Storgaard

doi:10.1038/ncomms10530

Cited by 94 publications

(85 citation statements)

References 41 publications

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“…We have defined a role for cyclin F in limiting H2A.X levels in G2 cells and attenuating apoptosis signals. This, together with previously described functions of cyclin F in regulating dNTP levels, controlling centrosome duplication, and other cell cycle events (D’Angiolella et al, 2010; D’Angiolella et al, 2012; Klein et al 2015; Elia et al, 2015; Sharma et al, 2011; Emanuele et al, 2011; Walter et al, 2016) indicate that cyclin F is a hub that regulates genome integrity and cell fate decisions in the mammalian cell.…”

Section: Discussionsupporting

confidence: 69%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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Summary SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent γH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress.

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Section: Discussionsupporting

confidence: 69%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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“…We recovered Cdc6 in a proteomic screen for Cyclin F interactors and have confirmed their binding by coIP (unpublished data) (Walter et al, 2016). The regulation of Cdc6 by Cyclin F prevents DNA re-replication.…”

Section: Discussionmentioning

confidence: 87%

“…The RRM2 subunit of ribonucleotide reductase is an important Cyclin F substrate that regulates genome stability (D'Angiolella et al, 2012). The exonuclease and DNA repair factor Exo1 was reported to be a Cyclin F substrate, as was the replication licensing factor Cdc6 (Elia et al, 2015; Walter et al, 2016). Cyclin F is unique among F-box proteins in that its transcript levels oscillate throughout the cell cycle.…”

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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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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“…Inhibition of pre-RC formation is mediated by steric exclusion of pre-RC assembly by direct cyclin binding [64,65,66] or CDK phosphorylation of the pre-RC components Orc2/6, Cdc6 and Cdt1 [65,66,67]. Phosphorylation of Orc2/6, Cdc6 and Cdt1 results in relocalization to the cytosol or ubiquitin proteasome system-mediated destruction that prevents inappropriate re-licensing at high CDK activity [66,68,69,70]. …”

Section: Replication Licensing and Prevention Of Re-replication Ismentioning

confidence: 99%

“…Increased CDK activity prevents initiation of DNA replication by phosphorylation of pre-RC proteins, DNA polymerase α and Ciz1 [66,68,69,70]. As high CDK activity is non-permissive for initiation of DNA replication, cells may require adaptive mechanisms to facilitate DNA replication at inhibitory CDK concentrations.…”

Section: Future Perspectivesmentioning

confidence: 99%

Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis

et al. 2016

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Precise duplication of the genome is a prerequisite for the health and longevity of multicellular organisms. The temporal regulation of origin specification, replication licensing, and firing at replication origins is mediated by the cyclin-dependent kinases. Here the role of Cip1 interacting Zinc finger protein 1 (Ciz1) in regulation of cell cycle progression is discussed. Ciz1 contributes to regulation of the G1/S transition in mammalian cells. Ciz1 contacts the pre-replication complex (pre-RC) through cell division cycle 6 (Cdc6) interactions and aids localization of cyclin A- cyclin-dependent kinase 2 (CDK2) activity to chromatin and the nuclear matrix during initiation of DNA replication. We discuss evidence that Ciz1 serves as a kinase sensor that regulates both initiation of DNA replication and prevention of re-replication. Finally, the emerging role for Ciz1 in cancer biology is discussed. Ciz1 is overexpressed in common tumors and tumor growth is dependent on Ciz1 expression, suggesting that Ciz1 is a driver of tumor growth. We present evidence that Ciz1 may contribute to deregulation of the cell cycle due to its ability to alter the CDK activity thresholds that are permissive for initiation of DNA replication. We propose that Ciz1 may contribute to oncogenesis by induction of DNA replication stress and that Ciz1 may be a multifaceted target in cancer therapy.

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SCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication

Cited by 94 publications

References 41 publications

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

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

Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis

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