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首页> 外文期刊>Cell cycle >A role for Chk2 in DNA damage induced mitotic delays in human colorectal cancer cells.
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A role for Chk2 in DNA damage induced mitotic delays in human colorectal cancer cells.

机译：Chk2在DNA损伤中诱导人大肠癌细胞有丝分裂延迟的作用。

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摘要

Progression into mitosis in the presence of DNA damage leads to spindle checkpoint (SAC) dependent mitotic delays and cytokinesis failure. In Drosophila embryos, DNA damage does not delay mitotic entry but triggers Checkpoint kinase-2 (Chk2) kinase dependent delays in mitotic exit. It is unclear if damage associated mitotic delays in human cells result from kinase signaling or breaks in centromere DNA that disrupt kinetochore function and activate the SAC. We show that transgenic expression of Human Chk2 in a Drosophila chk2 mutant background restores damage induced mitotic delays during early embryogenesis. Parental HCT116 colorectal cancer cells that progress into mitosis following DNA damage, due to either G(2) checkpoint adaptation or G(2) checkpoint abrogation by caffeine or the Chk1 inhibitor UCN-01, delay in mitosis and show high rates of cytokinesis failure. Significantly, these mitotic responses are suppressed in HCT116 chk2 knockout cells, and the response is restored by transgenic expression of wild type Chk2. However, both parental and chk2(-/-)HCT116 cells arrested in G(2) for prolonged periods by DNA damage prior to release from the G(2) block do show significant mitotic delays. Chk2 thus appears to have a conserved function in control of mitotic progression following G(2)/M transition with DNA damage. However, prolonged G(2) arrest with DNA damage can trigger Chk2 independent mitotic delays that may be secondary to kinetochore disruption.
机译：在存在DNA损伤的情况下发展为有丝分裂会导致纺锤体检查点（SAC）依赖性有丝分裂延迟和胞质分裂失败。在果蝇胚胎中，DNA损伤不会延迟有丝分裂进入，但会触发有丝分裂退出中的Checkpoint激酶2（Chk2）激酶依赖性延迟。目前尚不清楚是否由于激酶信号传导或着丝粒DNA的断裂而破坏了人类的细胞的有丝分裂延迟，从而破坏了线粒体的功能并激活了SAC。我们显示在果蝇chk2突变体背景中人类Chk2的转基因表达恢复早期胚胎发生过程中的损伤诱导的有丝分裂延迟。亲本的HCT116大肠癌细胞在DNA损伤后发展为有丝分裂，这是由于咖啡因或Chk1抑制剂UCN-01废除G（2）检查点适应或G（2）检查点废止，导致有丝分裂延迟，并显示出较高的胞质分裂失败率。重要的是，这些有丝分裂反应在HCT116 chk2基因敲除细胞中得到抑制，并且该反应通过野生型Chk2的转基因表达得以恢复。但是，亲本和chk2（-/-）HCT116细胞在G（2）中被DNA破坏之前被DNA破坏延长而被捕，然后才从G（2）块中释放出来，这确实显示出明显的有丝分裂延迟。因此Chk2似乎在G（2）/ M过渡与DNA损伤控制有丝分裂进程中具有保守的功能。但是，长时间的G（2）逮捕与DNA损伤可以触发Chk2独立的有丝分裂延迟，这可能是继动子的破坏。

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