Identification of Novel Human Cdt1-binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/C<sup>Cdh1</sup>

Sugimoto, Nozomi; Kitabayashi, Issay; Osano, Satoko; Tatsumi, Yasutoshi; Yugawa, Takashi; Narisawa‐Saito, Mako; Matsukage, Akio; Kiyono, Tohru; Fujita, Masatoshi

doi:10.1091/mbc.e07-09-0859

Cited by 63 publications

(81 citation statements)

References 72 publications

(140 reference statements)

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“…Overexpression of Cdh1, which activates APC Cdh1 , downregulated WT Cdt1 expression ( Supplementary Fig. S5H), as previously reported 17 . Cdh1 overexpression had a comparable effect also on DPEST Cdt1, indicating that the PEST domain does not influence APC Cdh1 -mediated degradation.…”

Section: W T δ P E S T V E C T V E C T W T δ P E S T V E C T V E C T supporting

confidence: 87%

“…A recent proteomic analysis revealed an unanticipated role of the E3 ligase APC Cdh1 in restraining Cdt1 activity 17 . D-boxes (the degrons recognized by this ligase) 40 in Cdt1 render the protein susceptible to Cdh1-mediated degradation.…”

Section: W T δ P E S T V E C T V E C T W T δ P E S T V E C T V E C T mentioning

confidence: 99%

“…Cdt1 regulation also involves the ubiquitin proteasome pathway and at least three different E3 ligases, namely SCF Skp2 (refs 13,14), CRL4 Cdt2 (refs 15,16) and APC Cdh1 (ref. 17), depending on the cellular context.…”

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confidence: 99%

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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

et al. 2013

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Cdt1 is required for loading the replicative DNA helicase MCM2/7, a process known as DNA replication licensing. Here we show that 129 mouse strains express a Cdt1 mutated allele with enhanced licensing activity. The mutation, named D 6 PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 D 6 PEST and more extensive deletions exhibit increased re-replication and transformation activities that are independent of the Geminin and E3 ligase pathways. This PEST domain negatively regulates cell cycledependent chromatin recruitment of Cdt1 in G2/M phases of the cell cycle. Mass spectrometry analysis indicates that Cdt1 is phosphorylated at sites within the deleted PEST domain during mitosis. This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity and suggests a mechanism by which the presence of Cdt1 in G2/M phases does not lead to premature origin licensing. These results also question the usage of 129 mouse strains for knockout analyses.

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Section: W T δ P E S T V E C T V E C T W T δ P E S T V E C T V E C T supporting

confidence: 87%

Section: W T δ P E S T V E C T V E C T W T δ P E S T V E C T V E C T mentioning

confidence: 99%

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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

et al. 2013

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“…4B). Its turnover is regulated by Cdh1-APCmediated degradation (31). At S phase onset, Cdt1 is degraded more efficiently by the activation of the ubiquitin ligase activity mediated by Cul4-DDB1-Cdt2 (32), and its level decreases dramatically; only low levels of Cdt1 remain.…”

Section: Discussionmentioning

confidence: 99%

Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication

Ballabeni

Zamponi²,

Moore

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cdc10-dependent transcript 1 (Cdt1) is an essential DNA replication protein whose accumulation at the end of the cell cycle promotes the formation of pre-replicative complexes and replication in the next cell cycle. Geminin is thought to be involved in licensing replication by promoting the accumulation of Cdt1 in mitosis, because decreasing the Geminin levels prevents Cdt1 accumulation and impairs DNA replication. Geminin is known to inhibit Cdt1 function; its depletion during G2 leads to DNA rereplication and checkpoint activation. Here we show that, despite rapid Cdt1 protein turnover in G2 phase, Geminin promotes Cdt1 accumulation by increasing its RNA and protein levels in the unperturbed cell cycle. Therefore, Geminin is a master regulator of cell-cycle progression that ensures the timely onset of DNA replication and prevents its rereplication.

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“…In addition to the Skp2 pathway, PCNA/ DDB1/Cul4-dependent signaling was found to degrade Cdt1 during S phase via the interaction of Cdt1 with PCNA (11)(12)(13)(14)(15). Recently, APC/C Cdh1 was proposed as a third ubiquitin ligase regulating Cdt1 degradation (16). Cdt1 is also targeted for degradation after DNA damage to stop licensing of new origins until after DNA repair.…”

mentioning

confidence: 99%

Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1

Zhang

Xing

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S-phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression.I n eukaryotic cells, DNA replication initiates from thousands of replication origins. Each origin acquires replication competence through the assembly of a prereplication complex (pre-RC) occurring in late mitosis and early G1 (1-3). Pre-RCs are assembled at the origins of DNA replication through the sequential loading of the initiation factors ORC, Cdc6, Cdt1, and MCM2-7 (4). In S phase, pre-RCs are sequentially acted on by two protein kinases, Cdc7 and Cdk2, which promote recruitment of proteins required for helicase activation and replisome assembly, leading to origin unwinding and DNA synthesis. To ensure that no replication origin fires more than once, the assembly of the replication apparatus at origins is tightly regulated by the cell cycle machinery. Among the most important of these regulatory mechanisms are the degradation of Cdt1 during S phase and the sequestration of Cdt1 by the geminin protein (5-7). Phosphorylation of Cdt1 by Cdk2 promotes its binding to SCF-Skp2 E3 ubiquitin ligase (8-10), which results in its degradation in S phase. In addition to the Skp2 pathway, PCNA/ DDB1/Cul4-dependent signaling was found to degrade Cdt1 during S phase via the interaction of Cdt1 with PCNA (11-15). Recently, APC/C Cdh1 was proposed as a third ubiquitin ligase regulating Cdt1 degradation (16). Cdt1 is also targeted for degradation after DNA damage to stop licensing of new origins until after DNA repair. Both the SCF-Skp2 complex and the Cul4-DDB1 complex have been reported to induce degradation of Cdt1 after UV irradiation (17,18).FOXO transcription factors are critical for the regulation of cell cycle arrest, cell death, and DNA damage repair. Ample evidence has suggested that FOXO exerts a negative effect on cell cycle progression. In dividing cells, overexpression of the active form of FOXO family members promotes cell cycle arrest at the G1/S boundary. Target genes that mediate FOXO-induced cell cycle arrest are the Cdk inhibitors p27KIP1 and p21 (in the presence of TGF-β), the Rb family member p130, and cyclin D1 and D2. The ectopically expressed active form of FOXO factors can cause G1 arrest both by up-regulat...

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Identification of Novel Human Cdt1-binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/C^Cdh1

Cited by 63 publications

References 72 publications

A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication

Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1

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Identification of Novel Human Cdt1-binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/CCdh1

Cited by 63 publications

References 72 publications

A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing

Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication

Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1

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Identification of Novel Human Cdt1-binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/C^Cdh1