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Poli J, et al.  (2012) dNTP pools determine fork progression and origin usage under replication stress. EMBO J 31(4):883-94

Abstract: 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.

Status: Published Type: Journal Article PubMed ID: 22234185

Topics addressed in this paper

Number of different genes curated to this paper: 17

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Topics Topics not linked to Genes Genes linked to topics (#1 - 10 )
ARS305 ASF1 CTF18 CTF4 DDC1 ELG1 MEC1 MRC1 RAD24 RAD52
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Topics Genes linked to topics (#11 - 17 )
RAD53 RAD9 RNR1 RRM3 RTT101 SGS1 SML1
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