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Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 6, 1657-1670 p.Article in journal (Refereed) Published
Abstract [en]

In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment.

Place, publisher, year, edition, pages
2016. Vol. 17, no 6, 1657-1670 p.
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Cell and Molecular Biology
URN: urn:nbn:se:umu:diva-127399DOI: 10.1016/j.celrep.2016.10.024ISI: 000386936200017PubMedID: 27806303OAI: diva2:1045602
Available from: 2016-11-10 Created: 2016-11-10 Last updated: 2016-12-06Bibliographically approved

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Kong, ZiqingMarjavaara, LisetteChabes, Andrei
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