title: Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis.
abstract: Precise duplication of the genome is a prerequisite for the health and longevity of multicellular organisms. The temporal regulation of origin specification, replication licensing, and firing at replication origins is mediated by the cyclin-dependent kinases. Here the role of Cip1 interacting Zinc finger protein 1 (Ciz1) in regulation of cell cycle progression is discussed. Ciz1 contributes to regulation of the G1/S transition in mammalian cells. Ciz1 contacts the pre-replication complex (pre-RC) through cell division cycle 6 (Cdc6) interactions and aids localization of cyclin A- cyclin-dependent kinase 2 (CDK2) activity to chromatin and the nuclear matrix during initiation of DNA replication. We discuss evidence that Ciz1 serves as a kinase sensor that regulates both initiation of DNA replication and prevention of re-replication. Finally, the emerging role for Ciz1 in cancer biology is discussed. Ciz1 is overexpressed in common tumors and tumor growth is dependent on Ciz1 expression, suggesting that Ciz1 is a driver of tumor growth. We present evidence that Ciz1 may contribute to deregulation of the cell cycle due to its ability to alter the CDK activity thresholds that are permissive for initiation of DNA replication. We propose that Ciz1 may contribute to oncogenesis by induction of DNA replication stress and that Ciz1 may be a multifaceted target in cancer therapy.
authors.affiliation: Faculty of Health and Medicine, Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YQ, UK. t.pauzaite@lancaster.ac.uk.
authors.forename: Tekle
authors.initials: T
authors.lastname: Pauzaite
authors.affiliation: Faculty of Health and Medicine, Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YQ, UK. u.thacker@lancaster.ac.uk.
authors.forename: Urvi
authors.initials: U
authors.lastname: Thacker
authors.affiliation: Faculty of Health and Medicine, Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YQ, UK. j.tollitt@lancaster.ac.uk.
authors.forename: James
authors.initials: J
authors.lastname: Tollitt
authors.affiliation: Faculty of Health and Medicine, Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YQ, UK. n.copeland@lancaster.ac.uk.
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Copeland
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects*; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004261:DNA Replication; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002843:Chromatin; C400423:Ciz1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D051357:Cyclin-Dependent Kinase 2
keywords: CDK; DNA replication stress; cancer; cell cycle; genome stability