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Regulating DNA Replication in Eukarya

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TLDR
Work from several organisms has revealed a conserved strategy whereby inactive replication complexes are assembled onto DNA during periods of low CDK and high APC activity but are competent to execute genome duplication only when these activities are reversed.
Abstract
DNA replication is tightly controlled in eukaryotic cells to ensure that an exact copy of the genetic material is inherited by both daughter cells. Oscillating waves of cyclin-dependent kinase (CDK) and anaphase-promoting complex/cyclosome (APC/C) activities provide a binary switch that permits the replication of each chromosome exactly once per cell cycle. Work from several organisms has revealed a conserved strategy whereby inactive replication complexes are assembled onto DNA during periods of low CDK and high APC activity but are competent to execute genome duplication only when these activities are reversed. Periods of high CDK and low APC/C serve an essential function by blocking reassembly of replication complexes, thereby preventing rereplication. Higher eukaryotes have evolved additional CDK-independent mechanisms for preventing rereplication.

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Book ChapterDOI

Regulation of Replication Origin Firing

TL;DR: A comparative analysis of the various cellular initiator proteins and the distinctive complexes involved in replication origin firing is included, as well as the diverse regulatory switches that ensure correctly timed and once per cell cycle genome duplication.
Posted ContentDOI

Phosphoregulation of Cdt1 in G2 and M phases prevents re-replication independently of Geminin

TL;DR: It is discovered that Cdt1 hyperphosphorylation during G2 and M phase is essential to prevent re-replication and DNA damage, the first example of direct Cdt 1 licensing activity control by post-translational modification.
References
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Journal ArticleDOI

Comprehensive Identification of Cell Cycle–regulated Genes of the Yeast Saccharomyces cerevisiae by Microarray Hybridization

TL;DR: A comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle is created, and it is found that the mRNA levels of more than half of these 800 genes respond to one or both of these cyclins.
Journal ArticleDOI

Genetic instabilities in human cancers

TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Journal ArticleDOI

Cell cycle, CDKs and cancer: a changing paradigm

TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
Journal ArticleDOI

The DNA Damage Response: Ten Years After

TL;DR: This work has witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage.
Journal ArticleDOI

Ubiquitin ligases: cell-cycle control and cancer

TL;DR: A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
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