Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase.
Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase.
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DOI：
10.1016/j.celrep.2016.10.024
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发表时间：
2016-11-01
期刊：
影响因子：
8.8
通讯作者：
Bell SD
中科院分区：
文献类型：
--
作者：
Liew LP;Lim ZY;Cohen M;Kong Z;Marjavaara L;Chabes A;Bell SD
在许多生物体中，羟基脲(HU)抑制I类核苷酸还原酶，导致脱氧核糖核苷三磷酸的细胞池减少。DNA前体水平的降低被认为是导致复制分叉停滞的原因。在用HU处理嗜热古生菌Sulfolobus solfararicus后，我们观察到剂量依赖性的细胞周期停滞、DNA双链断裂的积累、复制分叉停滞和重组结构水平的升高。然而，Sulfolobus有一个HU不敏感的II类核苷酸还原酶，我们揭示了HU处理对细胞DNA前体池没有显著影响。蛋白质和转录水平的分析揭示了复制启动和细胞分裂基因的特定子集的调节。值得注意的是，底物酶调节亚基的选择性丢失与复制起始的停止和复制分叉的停滞相关。此外，我们还发现了HU治疗引起的解毒反应的证据。Sulfolobus具有HU不敏感的II类核苷酸还原酶HU，HU可损害DNA复制，并对Sulfolobus细胞有毒性。HU处理会导致DNA底物酶Liew等人调节亚基的选择性丢失。证明羟基脲(HU)对嗜热古细菌Sulfolobus solfararicus有毒性。虽然古生菌缺乏Hu，Liew等人经典的I类核苷酸还原酶靶标，但证明了Hu导致Sulfolobus的DNA复制受损，与DNA Primase调节亚基的丢失有关。
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. Sulfolobus has a HU-insensitive class II ribonucleotide reductase HU impairs DNA replication and is toxic to Sulfolobus cells HU treatment leads to selective loss of the regulatory subunit of DNA primase Liew et al. demonstrate that hydroxyurea (HU) is toxic to the hyperthermophilic archaeon Sulfolobus solfataricus. Although archaea lack the classical class I ribonucleotide reductase target of HU, Liew et al., demonstrate HU causes impaired DNA replication in Sulfolobus, correlating with loss of the regulatory subunit of DNA primase.
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影响因子：
8.8
作者：
Samson RY;Xu Y;Gadelha C;Stone TA;Faqiri JN;Li D;Qin N;Pu F;Liang YX;She Q;Bell SD
通讯作者：
Bell SD
影响因子：
3.2
作者：
Frols, Sabrina;Gordon, Paul M. K.;Schleper, Christa
通讯作者：
Schleper, Christa
DOI：
10.1007/978-1-4939-2596-4_8
发表时间：
2015-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Jia, Shaodong;Marjavaara, Lisette;Chabes, Andrei
通讯作者：
Chabes, Andrei
DOI：
10.1073/pnas.0806414105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Duggin, Iain G.;McCallum, Simon A.;Bell, Stephen D.
通讯作者：
Bell, Stephen D.
影响因子：
1
作者：
Konstantinou, Eleni;Pashalidis, Ioannis;Kontoghiorghes, George J.
通讯作者：
Kontoghiorghes, George J.