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Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2012 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 31, no 4, 895-907 p.Article in journal (Refereed) Published
Abstract [en]

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. The EMBO Journal (2012) 31, 895-907. doi: 10.1038/emboj.2011.485; Published online 10 January 2012

Place, publisher, year, edition, pages
European Molecular Biology Organization , 2012. Vol. 31, no 4, 895-907 p.
Keyword [en]
deoxyribonucleoside triphosphates, DNA damage, DNA replication, mutagenesis, ribonucleotide reductase
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-54340DOI: 10.1038/emboj.2011.485ISI: 000300872100012OAI: diva2:519087
Available from: 2012-04-24 Created: 2012-04-24 Last updated: 2014-06-12Bibliographically approved

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Keszthelyi, AndreaMarjavaara, LisetteChabes, Andrei
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