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

Choudhury, Rajarshi; Bonacci, Thomas; Wang, Xianxi; Truong, Andrew; Arceci, Anthony; Zhang, Yanqiong; Mills, Christine A.; Kernan, Jennifer L.; Liu, Pengda; Emanuele, Michael J.

doi:10.1016/j.celrep.2017.08.099

Cited by 44 publications

(37 citation statements)

References 54 publications

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“…Lambda phosphatase treatment of the mitotically arrested U2OS cell lysates confirmed that both human ORC1 and CDC6 were phosphorylated, since after treatment the proteins moved faster in the gel, similar to Cyclin F protein which is known to be phosphorylated in mitosis (Choudhury et al, 2017;Mavrommati et al, 2018) ( Figure 3E).…”

Section: Cy Motif and Cdk Phosphorylation Sitesmentioning

confidence: 70%

Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication

Hossain

Bhalla

Stillman

2019

Preprint

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The initiation of DNA replication involves the cell cycle-dependent assembly and disassembly of protein complexes, including the Origin Recognition Complex (ORC) and CDC6 AAA+ ATPases. We report that multiple short, linear protein motifs (SLiMs) within intrinsically disordered regions in ORC1 and CDC6, including Cyclin-binding (Cy) motifs, mediate Cyclin-CDK dependent and independent protein-protein interactions, conditional on cell cycle phase. The ORC1 Cy motif mediates an auto-regulatory self-interaction, and the same Cy motif prevents CDC6 binding to ORC1 in mitosis, but then facilitates the destruction of ORC1 in S phase. In contrast, in G1, the CDC6 Cy motif promotes ORC1-CDC6 interaction independent of Cyclin-CDK protein phosphorylation. CDC6 interaction with ORC also requires a basic region of ORC1 that in yeast mediates ORC-DNA interactions. We also demonstrate that protein phosphatase 1 binds directly to a SLiM in ORC1, causing de-phosphorylation upon mitotic exit. Thus, Cy-motifs have wider roles, functioning as a ligand and as a degron.

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Section: Cy Motif and Cdk Phosphorylation Sitesmentioning

confidence: 70%

Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication

Hossain

Bhalla

Stillman

2019

Preprint

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“…Previous studies demonstrated that cyclin F functions as a key regulator of the cell cycle (Tetzlaff et al, 2004;Choudhury et al, 2016Choudhury et al, , 2017. Previous studies demonstrated that cyclin F functions as a key regulator of the cell cycle (Tetzlaff et al, 2004;Choudhury et al, 2016Choudhury et al, , 2017.…”

Section: Discussionmentioning

confidence: 99%

“…In an unperturbed cell cycle, cyclin F promotes the degradation of atypical E2Fs to allow a timely G2/M transition. Previous studies demonstrated that cyclin F functions as a key regulator of the cell cycle (Tetzlaff et al, 2004;Choudhury et al, 2016Choudhury et al, , 2017. CCNF, the gene encoding cyclin F, is highly conserved across different species.…”

Section: Discussionmentioning

confidence: 99%

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

et al. 2019

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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/CCdh1 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 SCFcyclin 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 SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin 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.

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“…Consistently, Cdh1 collaborates with the retinoblastoma tumor suppressor protein to restrict S‐phase entry (Fay et al , ; Binné et al , ; Buttitta et al , ; The et al , ), and single allelic loss of the Cdh1 gene promotes tumorigenesis in mice (García‐Higuera et al , ). We recently showed that Cdh1 degradation could be driven by upstream signaling through the oncogenic AKT kinase (Choudhury et al , ), which is activated in numerous cancers (Manning & Toker, ). Since, Cezanne is recurrently amplified/overexpressed in cancers, it could promote proliferation and perhaps impact chromosome stability, by antagonizing APC/C.…”

Section: Discussionmentioning

confidence: 99%

Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

et al. 2018

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The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.

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

Cited by 44 publications

References 54 publications

Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication

Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

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