Davidson MB, et al. (2012) Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype. EMBO J 31(4):895-907
Abstract: The integrity of the genome depends on diverse pathways that regulate DNA metabolism. Defects in these pathways result in genome instability, a hallmark of cancer. Deletion of ELG1 in budding yeast, when combined with hypomorphic alleles of PCNA results in spontaneous DNA damage during S phase that elicits upregulation of ribonucleotide reductase (RNR) activity. Increased RNR activity leads to a dramatic expansion of deoxyribonucleotide (dNTP) pools in G1 that allows cells to synthesize significant fractions of the genome in the presence of hydroxyurea in the subsequent S phase. Consistent with the recognized correlation between dNTP levels and spontaneous mutation, compromising ELG1 and PCNA results in a significant increase in mutation rates. Deletion of distinct genome stability genes RAD54, RAD55, and TSA1 also results in increased dNTP levels and mutagenesis, suggesting that this is a general phenomenon. Together, our data point to a vicious circle in which mutations in gatekeeper genes give rise to genomic instability during S phase, inducing expansion of the dNTP pool, which in turn results in high levels of spontaneous mutagenesis.
|Status: Published||Type: Journal Article||PubMed ID: 22234187|
Topics addressed in this paper
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|Topics||Topics not linked to Genes||Genes linked to topics (#1 - 10 )|
|Cell Cycle Phase Involved|
|Comparative genomic hybridization|
|Protein-Nucleic Acid Interactions|
|Topics||Genes linked to topics (#11 - 15 )|