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

News and Commentary Cell Death and Differentiation (2006) 13, 1052–1056. doi:10.1038/sj.cdd.4401932; published online 21 April 2006 Role of geminin: from normal control of DNA replication to cancer formation and progression? M Montanari1,2, M Macaluso1,3,4, A Cittadini2 and A Giordano1,3 1. 1Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Biotechnology, Temple University, Philadelphia, PA, USA 2. 2Institute of General Pathology- 'Giovanni XXIII' Cancer Research Center, Catholic University of Sacred Heart, Rome, Italy 3. 3Department of Human Pathology and Oncology, University of Siena, Siena, Italy 4. 4Section of Oncology, Department of Oncology, University of Palermo, Palermo, Italy Correspondence: A Giordano, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Biotechnology, Temple University, Biolife Sciences Building, Suite # 333,1900, North 12th Street, Philadelphia, PA 19122-6099, USA. Tel: +1-215-204-9520; Fax: +1-215-204-9519; E-mail: giordano@temple.edu 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?