Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype
2012 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 31, no 4, 895-907 p.Article in journal (Refereed) Published
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.
deoxyribonucleoside triphosphates, DNA damage, DNA replication, mutagenesis, ribonucleotide reductase
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:umu:diva-54340DOI: 10.1038/emboj.2011.485ISI: 000300872100012OAI: oai:DiVA.org:umu-54340DiVA: diva2:519087