Wild-type p53 inhibits replication-associated homologous recombination
Wild-type p53 inhibits replication-associated homologous recombination
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DOI：
10.1038/sj.onc.1205757
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发表时间：
2002-08-29
期刊：
影响因子：
8
通讯作者：
Wiesmüller, L
中科院分区：
文献类型：
--
作者：
Janz, C;Wiesmüller, L
在哺乳动物细胞中，当复制叉在DNA断裂或未修复的损伤处停止时，会刺激同源重组。肿瘤抑制因子p53独立于其转录活化功能下调同源重组，并与DNA重组和复制酶有关。为了研究与复制相关的重组，我们利用基于SV40病毒的实验，跟踪灵长类细胞感染后的同步事件。在病毒进入后不同时间的伽马射线治疗揭示了染色体间交换频率的增加，当DNA合成过程中引入损伤时。升高的重组频率被p53完全抑制。关于自发重组的下调，我们注意到在复制开始时需要活性p53分子。经过短暂的复制抑制剂处理后，我们观察到药物诱导的p53重组的抑制作用，特别是对延伸抑制剂aphidicolin。因此，我们提出p53是复制叉同源重组的一个监视因子，当它们由于内源性或外源性引入的损伤而停滞时。
In mammalian cells homologous recombination is stimulated, when the replication fork stalls at DNA breaks or unrepaired lesions. The tumor suppressor p53 downregulates homologous recombination independently of its transcriptional transactivation function and has been linked to enzymes of DNA recombination and replication. To study recombination with respect to replication, we utilized a SV40 virus based assay, to follow the synchronous events after primate cell infection. gamma-ray treatment at different times after viral entry unveiled an increase of interchromosomal exchange frequencies, when the damage was introduced during DNA synthesis. Elevated recombination frequencies were fully suppressed by p53. With respect to the downregulation of spontaneous recombination, we noticed a requirement for active p53 molecules, when replication started. After a transient treatment with replication inhibitors, we observed inhibition of the drug induced recombination by p53, particularly for the elongation inhibitor aphidicolin. Consequently, we propose that p53 is a surveillance factor of homologous recombination at replication forks, when they stall as a consequence of endogenous or of exogenously introduced damage.