A p53-dependent checkpoint pathway prevents rereplication
A p53-dependent checkpoint pathway prevents rereplication
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DOI：
10.1016/s1097-2765(03)00099-6
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发表时间：
2003-04-01
期刊：
影响因子：
16
通讯作者：
Dutta, A
中科院分区：
文献类型：
--
作者：
Vaziri, C;Saxena, S;Dutta, A
真核细胞控制 DNA 复制的起始，因此在 S 期发射一次的起点不会在同一细胞周期内再次发射。未能发挥这种控制会导致遗传不稳定。在这里，我们研究如何在正常哺乳动物细胞中防止复制，以及如何在肿瘤进展过程中克服这些机制。复制起始因子 Cdt1 和 Cdc6 以及细胞周期蛋白 A-cdk2 的过度表达可促进具有失活 p53 的人类癌细胞的复制，但不会促进具有功能性 p53 的细胞的复制。分布在整个基因组中的起源子集在第一个复制周期的 2-4 小时内重新激发。再复制的诱导通过 ATM/ATR/Chk2 DNA 损伤检查点途径激活 p53。 p53 通过诱导 cdk2 抑制剂 p21 抑制再复制。因此，p53依赖性检查点通路被激活以抑制再复制并促进遗传稳定性。
Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.