Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms

  title={Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms},
  author={Van Quy Nguyen and Carl Co and Joachim J Li},
The stable propagation of genetic information requires that the entire genome of an organism be faithfully replicated once and only once each cell cycle. In eukaryotes, this replication is initiated at hundreds to thousands of replication origins distributed over the genome, each of which must be prohibited from re-initiating DNA replication within every cell cycle. How cells prevent re-initiation has been a long-standing question in cell biology. In several eukaryotes, cyclin-dependent kinases… 
The role of protein kinases in DNA replication in Saccharomyces cerevisiae
Identifying substrates of both CDK and Cdc7 involved in DNA replication in the budding yeast Saccharomyces cerevisiae is set about, which reveals a previously unreported phosphorylation of Orc1 by a third kinase which has been identified as Casein Kinase II (CKII).
The many faces of redundancy in DNA replication control.
  • J. Diffley
  • Biology
    Cold Spring Harbor symposia on quantitative biology
  • 2010
This chapter describes these regulatory mechanisms in detail and explores the role of redundancy in the regulation of DNA replication, focusing on the budding yeast, Saccharomyces cerevisiae.
Regulation of Early Events in Chromosome Replication
Genome-wide analysis of re-replication reveals inhibitory controls that target multiple stages of replication initiation.
The findings allow us to categorize origins with respect to their propensity to reinitiate and demonstrate that pre-RC formation is not the only target for the mechanisms that prevent genomic re-replication.
Molecular causes and mechanisms of genomic instability in G1- deregulated cell cycle
It is concluded that in G1/S deregulated cells, chromosomal regions with an irregular distribution of inefficient origins are delayed in completing replication by lacking of functional origin redundancy that causes genomic instability.
Control of DNA replication licensing in a cell cycle
Geminin, whose degradation at the end of mitosis is essential for a new round of licensing, has been shown to bind Cdt1 and negatively regulate it, providing a new insight into the regulation of DNA replication in higher eukaryotes.
Preventing DNA over-replication: a Cdk perspective
The experimental induction of DNA over-replication is reviewed in the context of the quantitative model of Cdk action, and endoreduplication is viewed as a consequence of procedures that cause Cdk activity to fall below the threshold required to prevent licensing.
Distinct and sequential re-replication barriers ensure precise genome duplication
This work defines a new mechanism that prevents re-replication through hyperphosphorylation of the essential MCM loading protein, Cdt1, and demonstrates that Cyclin A/CDK1 can hyperph phosphorylate Cdt 1 to inhibit MCM re-loading in G2 phase.
Mechanisms involved in regulating DNA replication origins during the cell cycle and in response to DNA damage.
The role of cyclin-dependent kinases in limiting DNA replication origin usage to once per cell cycle in the budding yeast Saccharomyces cerevisiae is summarized and the possibility that checkpoint regulation of late-origin firing operates through the regulation of the acetylation state is attempted.


Persistent initiation of DNA replication and chromatin-bound MCM proteins during the cell cycle in cdc6 mutants.
A newly isolated cdc6 mutant displays promiscuous initiation of DNA replication, increased nuclear DNA content, and constant MCM protein association with chromatin throughout the cell cycle, suggesting that Cdc6p is a key mediator of once-per-cell-cycle control of DNA replicate.
Regulation of chromosome replication.
The checkpoint mechanisms that function to preserve the integrity of the genome when the normal course of genome duplication is perturbed by factors that damage the DNA or inhibit DNA synthesis are described.
The Cdt1 protein is required to license DNA for replication in fission yeast
Genes related to Cdt1 have been found in Metazoa and plants, suggesting that the cooperation of Cdc6/Cdc18 with Cdt 1 to load MCM proteins onto chromatin may be a generally conserved feature of DNA licensing in eukaryotes.
Regulation of the replication initiator protein p65cdc18 by CDK phosphorylation.
Cyclin-dependent kinases (CDKs) promote the initiation of DNA replication and prevent reinitiation before mitosis, presumably through phosphorylation of key substrates at origins of replication. In
Control of DNA Rereplication via Cdc2 Phosphorylation Sites in the Origin Recognition Complex
It is proposed that cell cycle-regulated phosphorylation of the ORC provides a safety net to prevent DNA rereplication and resulting genetic instability.
cdc18+ regulates initiation of DNA replication in Schizosaccharomyces pombe.
The data indicate that the synthesis of Cdc18 protein is a critical rate-limiting step in the initiation of DNA replication during each cell cycle, and the extreme lability of the protein may contribute to the prevention of reinitiation.