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.

Highlights

  • Regulation of DNA replication is required to ensure that the genome is precisely duplicated prior to segregation into daughter cells

  • We present evidence that Cip1 interacting Zinc finger protein 1 (Ciz1) may contribute to deregulation of the cell cycle due to its ability to alter the cyclin-dependent kinase (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

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Summary

Introduction

Regulation of DNA replication is required to ensure that the genome is precisely duplicated prior to segregation into daughter cells. Faithful duplication of the genome is central to the long-term health of an organism This process is regulated at multiple levels to ensure near-perfect chromosome duplication with error rates at less than 1 per billion bases copied [1]. This level of precision requires highly orchestrated and stratified mechanisms to ensure that DNA replication occurs once and only once per cell cycle.

Temporal Regulation of Replication Complex Assembly
Replisome formation
Discovery of Ciz1 and Its Role in Cell Cycle Regulation
Ciz1 Is a Driver of Tumor Growth
Ciz1-Mediated Transcriptional Regulation of Tumorigenesis
Deregulation of CDK Activity Promotes DNA Replication Stress
Does Ciz1 Contribute to Tumorigenesis by Inducing DNA Replication Stress?
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