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dNTP pools determine fork progression and origin usage under replication stress
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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, 883-894 p.Article in journal (Refereed) Published
Abstract [en]

Intracellular deoxyribonucleoside triphosphate (dNTP) pools must be tightly regulated to preserve genome integrity. Indeed, alterations in dNTP pools are associated with increased mutagenesis, genomic instability and tumourigenesis. However, the mechanisms by which altered or imbalanced dNTP pools affect DNA synthesis remain poorly understood. Here, we show that changes in intracellular dNTP levels affect replication dynamics in budding yeast in different ways. Upregulation of the activity of ribonucleotide reductase (RNR) increases elongation, indicating that dNTP pools are limiting for normal DNA replication. In contrast, inhibition of RNR activity with hydroxyurea (HU) induces a sharp transition to a slow-replication mode within minutes after S-phase entry. Upregulation of RNR activity delays this transition and modulates both fork speed and origin usage under replication stress. Interestingly, we also observed that chromosomal instability (CIN) mutants have increased dNTP pools and show enhanced DNA synthesis in the presence of HU. Since upregulation of RNR promotes fork progression in the presence of DNA lesions, we propose that CIN mutants adapt to chronic replication stress by upregulating dNTP pools.

Place, publisher, year, edition, pages
2012. Vol. 31, no 4, 883-894 p.
Keyword [en]
checkpoints, DNA damage, dNTPs, hydroxyurea, replication stress
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-54339DOI: 10.1038/emboj.2011.470ISI: 000300872100011OAI: oai:DiVA.org:umu-54339DiVA: diva2:523452
Available from: 2012-04-24 Created: 2012-04-24 Last updated: 2017-12-07Bibliographically approved

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Tsaponina, OlgaKeszthelyi, AndreaChabes, Andrei

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Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)
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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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