Essential role for mevalonate synthesis in DNA replication.
Essential role for mevalonate synthesis in DNA replication.
复制标题
甲羟戊酸合成在 DNA 复制中的重要作用。
DOI：
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复制
发表时间：
1979
影响因子：
11.1
通讯作者：
M. Siperstein
中科院分区：
文献类型：
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作者：
V. Quesney;M. Wiley;M. Siperstein
在同步培养的BHK-21细胞中研究了3-羟基-3-甲基戊二酰（HMG）CoA还原酶活性[甲羟戊酸：NADP（+）氧化还原酶（CoA-酰化），EC 1.1.1.34]与DNA合成之间的关系。在细胞复制的24小时期间，两个阶段的加速胸苷掺入DNA对应于两个S期的细胞周期发生。HMG CoA还原酶活性的显著增加在这些DNA合成峰中的每一个峰时或之前被一致地观察到。此外，当HMG CoA还原酶活性被竞争性抑制剂康帕汀抑制时，DNA合成的正常S期爆发被特异性地完全阻止。最后，通过加入甲羟戊酸（HMG CoA还原酶反应的产物），可以在几分钟内完全逆转致密化蛋白诱导的DNA合成抑制。相比之下，添加富含胆固醇的脂蛋白对致密蛋白处理的细胞中的DNA合成没有影响。这些数据表明，HMG CoA还原酶活性，并因此产生甲羟戊酸，在DNA的合成中起着至关重要的作用，特别是在细胞周期的S期。此外，结果表明，甲羟戊酸在调节DNA复制中的这种功能不依赖于其转化为胆固醇。
The relationship between 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity [mevalonate:NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34] and DNA synthesis was studied in synchronized cultures of BHK-21 cells. During a 24-hr period of cell replication, two phases of accelerated thymidine incorporation into DNA corresponding to two S phases of the cell cycle occurred. A marked increase in activity of HMG CoA reductase was consistently observed at or just prior to each of these peaks of DNA synthesis. Moreover, when HMG CoA reductase activity was suppressed by the competitive inhibitor compactin, the normal S-phase burst of DNA synthesis was specifically and totally prevented. Finally, the compactin-induced inhibition of DNA synthesis could be completely reversed within minutes by the addition of mevalonate, the product of the HMG CoA reductase reaction. By contrast, addition of cholesterol-rich lipoproteins had no effect upon DNA synthesis in compactin-treated cells. These data demonstrate that HMG CoA reductase activity, and therefore the production of mevalonate, plays an essential role in the synthesis of DNA specifically during the S phase of the cell cycle. Moreover, the results indicate that this function of mevalonate in regulating DNA replication is independent of its conversion to cholesterol.