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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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Journal ArticleDOI

On the Interplay of the DNA Replication Program and the Intra-S Phase Checkpoint Pathway.

TL;DR: Current models on how the intra-S phase checkpoint regulates the replication program in budding yeast and metazoan models, including early embryos with rapid S phases are summed up.
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The evolutionary plasticity of chromosome metabolism allows adaptation to constitutive DNA replication stress.

TL;DR: It is suggested that the evolutionary plasticity of chromosome metabolism has implications for genome evolution in natural populations and cancer.
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Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases

TL;DR: The current knowledge of the molecular genetics of replisome dysfunction disorders is reviewed and recent mechanistic insights into their pathogenesis are discussed, with a focus on the specific steps of DNA replication affected in these human diseases.
Journal ArticleDOI

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

TL;DR: In this paper, the main role of cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E and CDK2 causes replication stress and genomic instability in human cancer.
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Identification of genes that are essential to restrict genome duplication to once per cell division.

TL;DR: DePamphilis et al. as discussed by the authors identified 42 genes that prevent EDR in cancer cells with undetectable chromosomal instability and 14 genes have been shown to prevent aneuploidy in mice.
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.
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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.
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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.
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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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