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dNTP pools determine fork progression and origin usage under replication stress
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
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2012 (engelsk)Inngår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 31, nr 4, s. 883-894Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2012. Vol. 31, nr 4, s. 883-894
Emneord [en]
checkpoints, DNA damage, dNTPs, hydroxyurea, replication stress
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-54339DOI: 10.1038/emboj.2011.470ISI: 000300872100011OAI: oai:DiVA.org:umu-54339DiVA, id: diva2:523452
Tilgjengelig fra: 2012-04-24 Laget: 2012-04-24 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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