Caenorhabditis elegans Geminin Homologue Participates in Cell Cycle Regulation and Germ Line Development

Yanagi, Ken-ichiro; Mizuno, Takeshi; Tsuyama, Takashi; Tada, Shusuke; Iida, Yumi; Sugimoto, Akihiro; Eki, Toshihiko; Enomoto, Takemi; Hanaoka, Fumio

doi:10.1074/jbc.c500070200

Cited by 39 publications

(54 citation statements)

References 40 publications

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“…2C). This has been observed in D. melanogaster, C. elegans, and human cells when geminin is depleted and in C. elegans embryos when CUL4 is knocked down (Zhong et al 2003;Melixetian et al 2004;Yanagi et al 2005). Second, while the mitotic index of the dtl mutants is not significantly different from wildtype controls (Fig.…”

Section: Disruption Of Dtl Causes Multiple Cell Cycle Defectsmentioning

confidence: 80%

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

151

150

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Checkpoint genes maintain genomic stability by arresting cells after DNA damage. Many of these genes also control cell cycle events in unperturbed cells. By conducting a screen for checkpoint genes in zebrafish, we found that dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint. We subsequently found that dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication. Both the checkpoint and replication roles are conserved in human DTL. Our data indicate that the rereplication reflects a requirement for DTL in regulating CDT1, a protein required for prereplication complex formation. CDT1 is degraded in S phase to prevent rereplication, and following DNA damage to prevent origin firing. We show that DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation in unperturbed cells and following DNA damage. The cell cycle defects of Dtl-deficient zebrafish are suppressed by reducing Cdt1 levels. In contrast, the early G2/M checkpoint defect appears to be Cdt1-independent. Thus, DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint.

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Section: Disruption Of Dtl Causes Multiple Cell Cycle Defectsmentioning

confidence: 80%

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

151

150

View full text Add to dashboard Cite

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“…Geminin was originally described as a bi-functional molecule; the N-terminus implicated in neural-cell fate determination [7], the C-terminus and central regions involved in DNA replication and cell cycle progression [13] in the Xenopus embryo. Geminin also binds polycomb and Brahma proteins to regulate gene expression [33,9]; it binds Hox and Six proteins to influence patterning of the embryo [8,9,36]; our in vitro results (Slawny and O'Shea this issue) suggest that it also binds nuclear TLEs to control the Wnt-signaling cascade. Ultimately, competition for partner proteins in a position-or stage-restricted manner may place Geminin in a unique position to influence the differentiation of many tissues.…”

Section: Discussionmentioning

confidence: 95%

Geminin Is Required for Epithelial to Mesenchymal Transition at Gastrulation

Boer

O’Shea

2012

Stem Cells and Development

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Geminin is a multifunctional protein previously suggested to both maintain the bone morphogenetic protein inhibition required for neural induction and to control cell-cycle progression and cell fate in the early embryo. Since Geminin is required in the blastocyst on E3.5, we employed shRNA to examine its role during postimplantation development. Geminin knockdown inhibited the epithelial to mesenchymal transition (EMT) required at gastrulation and neural crest delamination, resulting in anterior-posterior axis and patterning defects, while overexpression promoted EMT at both locations. Geminin was negatively correlated with expression of E-cadherin, which is critically involved in controlling epithelial architecture. In addition, Geminin expression level was correlated with Wnt signaling and expression of the Wnt target gene Axin2 and with Msx2, and negatively correlated with the expression of Bmp4 and Neurog1 in quantitative reverse transcriptase-polymerase chain reaction analysis of RNAs from individual embryos. These results suggest that in addition to patterning the early embryo, Geminin plays a previously unrecognized role in EMT via its ability to affect Wnt signaling and E-cadherin expression.

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“…GMN-1 is able to associate with C. elegans CDT1, to inhibit the interaction between mouse Cdt1 and Mcm6, and to bind in vitro homeobox proteins (NOB-1 and CEH-32) in order to control the development and differentiation in this organism. 49 However, the geminin-cdt1 interaction is conserved through the metazoans, although the affinity of GMN-1 for CDT1 is rather weak compared to Xenopus or mouse system. 49 Probably, during the evolution, geminin could be evolved in these taxa to regulate the proliferation and differentiation by directly interacting with cdt1 and homeobox proteins or by an unknown cell cycle regulator.…”

Section: Geminin: Multiple Functions In Development and Differentiationmentioning

confidence: 99%

“…49 However, the geminin-cdt1 interaction is conserved through the metazoans, although the affinity of GMN-1 for CDT1 is rather weak compared to Xenopus or mouse system. 49 Probably, during the evolution, geminin could be evolved in these taxa to regulate the proliferation and differentiation by directly interacting with cdt1 and homeobox proteins or by an unknown cell cycle regulator.…”

Section: Geminin: Multiple Functions In Development and Differentiationmentioning

confidence: 99%

Role of geminin: from normal control of DNA replication to cancer formation and progression?

Montanari

Macaluso

Cittadini³

et al. 2006

Cell Death Differ

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The normal cell proliferation involves the passage through a series of finely regulated phases that are known as cell cycle checkpoints. In order to carry out a correct replication, the eukaryotic cell undergoes to a series of events ensuring that each copy of duplicated chromosome exactly segregates in each of daughter cells. 1,2 A main critical control of the cell cycle is to ensure that the DNA replication takes place and that it is followed by mitosis, once for each cell cycle. Alterations in the expression of genes that regulate the cell cycle can lead to malignant transformation and tumor progression by perturbing cell proliferation and/ or genomic stability. 3,4 The normal progression through the cell cycle is a critical step for the survival of eukaryotic cells, in which the initiation of DNA replication is under the tight control of several factors that ensure the exact duplication of chromosomes in S phase and their subsequent segregation in phase M. The strict regulation of the cell cycle combined with the presence of a licensing phase, in which the chromatin becomes licensed to be replicated, leads to the existence of a single DNA replication start site for each round of replication. 5 In this complicated network of signals regulating the cell cycle and maintaining genome integrity, the geminin protein is considered one of the main players. However, if the geminin acts as oncosuppressor gene or as a proto-oncogene is still an open question.In this article, we will report the mechanism by which geminin controls that the huge quantity of eukaryotes DNA, distributed over multiples chromosomes, is replicated once and once only for each cell cycle. Moreover, we will open and discuss an important question: what role does geminin play in cancer formation and progression? Does geminin act as an oncosuppressor, as a proto-oncogene or exhibit both roles? Geminin in the LicensingThe replication of eukaryotic genome is a complex process strictly regulated by an intricate intracellular and extracellular signaling network, which controls different phenomena such as cell proliferation, differentiation and apoptosis. 6,7 All these processes have a common function: the regulation of the initial phase of DNA replication. During this event, specific proteins sequentially assemble onto the replication origin by forming specific replicative complexes (pre-RC), which allow for the chromatin to be competent (licensed) for the next DNA replication step of the cell cycle. 8 Geminin is a 25 kDa nuclear protein that functions by inhibiting DNA replication. 9 During specific phases of the cell cycle, geminin is able to bind to Cdt1 protein and inhibits pre-RC formation. 10 In eukaryotes, the origins of replication are bound by a complex of six proteins, evolutionally well conserved among different species. 11,12 These proteins constitute the origin recognition complex (ORC) (1-6), a complex of proteins essential for the initiation of DNA replication, which was first identified in Saccharomyces cerevisiae as protein that bound t...

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Caenorhabditis elegans Geminin Homologue Participates in Cell Cycle Regulation and Germ Line Development

Cited by 39 publications

References 40 publications

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Geminin Is Required for Epithelial to Mesenchymal Transition at Gastrulation

Role of geminin: from normal control of DNA replication to cancer formation and progression?

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