Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents
Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents
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DOI：
10.1038/sj.onc.1207873
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发表时间：
2004-08-26
期刊：
影响因子：
8
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Nitta, M;Kobayashi, O;Saya, H
有丝分裂突变是损伤DNA的抗肿瘤药物诱导癌细胞死亡的重要机制。细胞周期的G(1)和G(2)检查点的缺陷促进了这一过程，这种缺陷在大多数癌细胞中很明显，并允许细胞在DNA损伤的情况下进入有丝分裂。我们现在已经描述了p53缺陷癌细胞中dna损伤剂诱导的有丝分裂灾难的动力学。带有DNA损伤进入有丝分裂的细胞在中期短暂停滞超过10小时，没有染色体分离，随后直接从中期死亡。在这些中期阻滞的突变前细胞中，后期促进复合体似乎失活，BubR1持续定位于着丝点，表明纺锤体检查点在DNA损伤后被激活。此外，DNA受损细胞中的BubR1或Mad2 RNA干扰对纺锤体检查点功能的抑制导致细胞免于灾难性死亡和随后的异常有丝分裂。因此，p53缺陷癌细胞的纺锤体检查点功能障碍可能是抵抗dna损伤治疗剂的关键因素。
Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G(1) and G(2) checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10 h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint function by BubR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.