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

Abstract

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...

The Anti-Proliferative Effects of Enterolactone in Prostate Cancer Cells: Evidence for the Role of DNA Licencing Genes, mi-R106b Cluster Expression, and PTEN Dosage

“…However, the effect of altering the GMNN/CDT1 balance in tumourigenic cells (which express higher levels of these genes compared to normal cells [31]) is unclear as there is debate about how the GMNN/CDT1 balance influences the development and progression of cancer [26,27,28,39,40]. Additionally we have also shown that the expression of MCM2 and MCM7 is reduced by ENL in the prostate cell lines used, and this may be linked altered CDT1 expression as CDT1 is required for the loading of the MCM complex during the initiation of DNA replication [24].…”

“…The loading of this MCM complex is facilitated, in part, by chromatin licensing and DNA replication factor 1 (CDT1), which is itself negatively regulated by geminin (GMMN). Abnormal expression of GMNN, CDT1, and MCM2 and 7 have been linked with the malignant progression of prostate cancer [25,26,27,28,29,30,31]. Another key signalling pathway disrupted in prostate cancer is the phosphoinositide-3-kinase (PI3K)-AKT signalling pathway.…”

A Cdt1–geminin complex licenses chromatin for DNA replication and prevents rereplication during S phase in Xenopus

“…Thus, accurate control of the balance between Cdt1 and geminin is essential for cell survival and genetic stability. Using gene expression profiling in cancer diagnostics, Cdt1 and geminin have become important targets (for a review, see Montanari et al , 2006). We suggest that the evaluation of their ratio might be as important to predict clinical outcome as the simple evaluation of their absolute levels.…”

Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma: prognostic implications

“…These phenotypes were relatively well associated with the histologically poor degree of tumor differentiation and tumor local invasiveness. Geminin, which is also one of the DNA replication licensing factors, is expressed during the S, G2, and M phases but not in G0 and G1 phases, and is degraded at M phase without playing a specific role in cell division control (36). It has been suggested that Geminin might provide useful information about tumor proliferation activities that is equal or superior to that of MCM proteins or Ki-67.…”