Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase

被引：21

作者：

Liew, Li Phing ^{[1
]}

Lim, Zun Yi ^{[2
]}

Cohen, Matan ^{[3
]}

Kong, Ziqing ^{[4
]}

Marjavaara, Lisette ^{[4
]}

Chabes, Andrei ^{[4
,5
]}

Bell, Stephen D. ^{[2
,3
]}

机构：

[1] Sir William Dunn Sch Pathol, South Pk Rd, Oxford OX1 3RE, England

[2] Indiana Univ, Dept Mol & Cellular Biochem, Simon Hall MSB,212 South Hawthorne Dr, Bloomington, IN 47405 USA

[3] Indiana Univ, Dept Biol, Simon Hall MSB,212 South Hawthorne Dr, Bloomington, IN 47405 USA

[4] Umea Univ, Dept Med Biochem & Biophys, SE-90197 Umea, Sweden

[5] Umea Univ, Lab Mol Infect Med Sweden, SE-90197 Umea, Sweden

来源：

CELL REPORTS | 2016年 / 17卷 / 06期

基金：

英国惠康基金; 瑞典研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

ARCHAEON SULFOLOBUS-SOLFATARICUS; DEOXYCYTIDYLATE DEAMINASE; PRIMER SYNTHESIS; DNA-REPLICATION; HEL308; HELICASE; CELL-DIVISION; ISLANDICUS; PROTEINS; PRIMASE; DAMAGE;

D O I：

10.1016/j.celrep.2016.10.024

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1657 / 1670

页数：14

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