title: Exploring and exploiting the systemic effects of deregulated replication licensing.
abstract: Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Theodoros G
authors.initials: TG
authors.lastname: Petrakis
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Eirini-Stavroula
authors.initials: ES
authors.lastname: Komseli
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Papaioannou
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Vougas
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Polyzos
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Myrianthopoulos
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens, Greece.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Thanos
authors.affiliation: FIRC (Fondazione Italiana per la Ricerca sul Cancro) Institute of Molecular Oncology (IFOM), Milan, Italy.
authors.forename: Dana
authors.initials: D
authors.lastname: Branzei
authors.affiliation: Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Townsend
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: vgorg@med.uoa.gr.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D004261:DNA Replication; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics*
keywords: Cancer; Cdc6; Cdt1; Replication licensing factors; Replication stress