Cdt1 and Geminin in cancer: markers or triggers of malignant transformation?

Petropoulou, Chariklia; Kotantaki, Panoraia; Karamitros, Dimitris; Taraviras, Stavros

doi:10.2741/3018

Cited by 64 publications

(62 citation statements)

References 65 publications

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“…For example, the combination of an in vivo licensing assay with depletion or overexpression of specific factors may allow the identification of novel factors that block or enhance DNA licensing. Moreover, given that Cdt1/Cdc6 overexpression and, thus, overlicensing of DNA has been associated with malignant transformation and tumorigenesis, the licensing system has been proposed as a novel molecular target for anticancer drug design (23,25). An in vivo licensing assay may offer a new approach for cell-based screens for the identification and validation of antitumor compounds and drugs under development that will block DNA licensing and, thus, DNA replication in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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Multi-step Loading of Human Minichromosome Maintenance Proteins in Live Human Cells

Symeonidou

Kotsantis

Roukos

et al. 2013

Journal of Biological Chemistry

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Background: MCM2-7 loading onto chromatin licenses origins for replication. Results: MCMs exhibit transient interactions with chromatin in late mitosis, stable binding in G 1 phase and increased loading in late G 1 phase. Conclusion: Multilevel regulation of MCM2-7 loading to chromatin occurs during mitosis and preceding the G 1 /S phase transition. Significance: The dynamics of the DNA licensing system within live human cells reveal multiple control points.

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Section: Discussionmentioning

confidence: 99%

“…The timing and extent of MCM loading onto chromatin must be accurately controlled through the cell cycle and coordinated with S phase onset. Both underlicensing and overlicensing have been linked to DNA replication stress, genomic instability, and malignant transformation (23)(24)(25).…”

mentioning

confidence: 99%

Multi-step Loading of Human Minichromosome Maintenance Proteins in Live Human Cells

Symeonidou

Kotsantis

Roukos

et al. 2013

Journal of Biological Chemistry

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“…However, it is well known in other eukaryotes and more specifically in human cells that altered regulation of DNA replication licensing due to changes in CDT1 activity results in aberrant replication, activates DNA damage checkpoints and predisposes for malignant transformation (Petropoulou et al, 2008). Therefore, regulation of pre-RC activity is likely to be crucial for the maintenance of genome integrity also in plants.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Role of Arabidopsis CDT1 Proteins in Gametophyte Development and Maintenance of Genome Integrity

et al. 2012

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Meristems retain the ability to divide throughout the life cycle of plants, which can last for over 1000 years in some species. Furthermore, the germline is not laid down early during embryogenesis but originates from the meristematic cells relatively late during development. Thus, accurate cell cycle regulation is of utmost importance to avoid the accumulation of mutations during vegetative growth and reproduction. The Arabidopsis thaliana genome encodes two homologs of the replication licensing factor CDC10 Target1 (CDT1), and overexpression of CDT1a stimulates DNA replication. Here, we have investigated the respective functions of Arabidopsis CDT1a and CDT1b. We show that CDT1 proteins have partially redundant functions during gametophyte development and are required for the maintenance of genome integrity. Furthermore, CDT1-RNAi plants show endogenous DNA stress, are more tolerant than the wild type to DNA-damaging agents, and show constitutive induction of genes involved in DNA repair. This DNA stress response may be a direct consequence of reduced CDT1 accumulation on DNA repair or may relate to the ability of CDT1 proteins to form complexes with DNA polymerase ε, which functions in DNA replication and in DNA stress checkpoint activation. Taken together, our results provide evidence for a crucial role of Arabidopsis CDT1 proteins in genome stability.

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“…In normal cells, CDT1 activity is precisely controlled by its negative regulator Geminin, which ensures the firing of each replication origin to occur once per cell cycle. CDT1 accumulation, as a result of RBX1 silencing, would disrupt this fine balance, thus causing aberrant replication to trigger DNA damage checkpoints (52). Indeed, a recent study showed that CDT-1 overexpression in human cancer cells causes DSB to trigger DDR (31), whereas overexpression of Double-arked (Dup), the Drosophila ortholog of CDT1, causes DNA re-replication and DNA damage (53).…”

Section: Rbx-1 Silencing Induces Ddr and Lethal Phenotypes In C Elegmentioning

confidence: 99%

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Jia

Bickel

et al. 2011

Journal of Biological Chemistry

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RBX1 (RING box protein 1), also known as ROC1 (Regulator of Cullin 1), is an essential component of SCF (Skp1/Cullins/Fbox) E3 ubiquitin ligases, which target diverse proteins for proteasome-mediated degradation. Our recent study showed that RBX1 silencing triggered a DNA damage response (DDR) leading to G 2 -M arrest, senescence, and apoptosis, with the mechanism remaining elusive. Here, we show that, in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G 2 arrest, and, eventually, aneuploidy. Whereas CHK1 activation by RBX1 silencing is responsible for the G 2 arrest, enhanced DNA damage renders cancer cells more sensitive to radiation. In Caenorhabditis elegans, RBX-1 silencing causes CDT-1 accumulation, triggering DDR in intestinal cells, which is largely abrogated by simultaneous CDT-1 silencing. RBX-1 silencing also induces lethality during development of embryos and in adulthood. Thus, RBX1 E3 ligase is essential for the maintenance of mammalian genome integrity and the proper development and viability in C. elegans. SCF (Skp1/Cullins/F-box; also known as CRL (Cullin-RING Ligase) E3 ubiquitin ligases are the largest multiunit E3 ligases that promote the degradation of numerous short-lived cellular proteins, including cell cycle regulators, transcription factors, signal transducers, and oncogene/tumor suppressors (1, 2). A recent global protein stability profiling analysis identified ϳ350 potential SCF substrates, the majority of which were previously unidentified (3). Most recently, a study of SCF inactivation by a small molecule inhibitor of cullin neddylation suggested that up to 20% of ubiquitinated cellular proteins are mediated by SCF E3 for proteasome degradation (4). Thus, SCF E3 ubiquitin ligases regulate many aspects of cellular functions and biological processes under physiological conditions. Dysfunction of SCF is involved in the pathogenesis of a variety of diseases, including cancer (2, 5).The core of SCF ubiquitin ligases is a complex of RBX1-cullins (6). RBX1 consists of 108 amino acids with a C-terminal RING-H2 finger domain required for zinc ion binding and ligase activity (7-9). Crystal structure studies revealed that RBX1 complexes with cullin/F-box proteins form functional SCF E3 ligases that transfer ubiquitin from E2 to specific substrates for proteasome-targeted degradation (10). Previous studies have shown that RBX1 interacts with all seven cullin family members to activate E3 ubiquitin ligases and regulate numerous biological processes by promoting timely degradation of cellular substrates (9, 11).As an essential component of SCF E3 ligase, RBX1 plays a critical role in development. In yeast, deletion of Hrt1, the yeast homolog of RBX1, causes lethality, which can be rescued by human RBX1 or RBX2/SAG (Sensitive to Apoptosis gene) (9,12,13). In Caenorhabditis elegans, RBX-1 is crucial for cell cycle progression and chromosome metabolism, and RBX-1 silencing results in embryonic d...

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Cdt1 and Geminin in cancer: markers or triggers of malignant transformation?

Cited by 64 publications

References 65 publications

Multi-step Loading of Human Minichromosome Maintenance Proteins in Live Human Cells

Multi-step Loading of Human Minichromosome Maintenance Proteins in Live Human Cells

Evidence for a Role of Arabidopsis CDT1 Proteins in Gametophyte Development and Maintenance of Genome Integrity

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

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