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首页> 外文期刊>Cell cycle >Mitotic DNA damage response: Polo-like kinase-1 is dephosphorylated through ATM-Chk1 pathway.
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Mitotic DNA damage response: Polo-like kinase-1 is dephosphorylated through ATM-Chk1 pathway.

机译：有丝分裂DNA损伤反应：Polo样激酶1通过ATM-Chk1途径去磷酸化。

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摘要

DNA damage during the cell division cycle can activate ATM/ATR and their downstream kinases that are involved in the checkpoint pathway, and cell growth is halted until damage is repaired. As a result of DNA damage induced in mitotic cells by doxorubicin treatment, cells accumulate in a G(2)-like phase, not in mitosis. Under these conditions, two mitosis-specific kinases, Cdk1 and Plk1, are inhibited by inhibitory phosphorylation and dephosphorylation, respectively. G(2)-specific phosphorylation of Cdc25 was increased during incubation after mitotic DNA damage. Inhibition of Plk1 through dephosphorylation was dependent on ATM/Chk1 activity. Depleted expression of ATM and Chk1 was achieved using small hairpin RNA (shRNA) plasmid constructs. In this condition, damaged mitotic cells did not accumulated in a G(2)-like stage, and entered into G(1) phase without delay. Protein phosphatase 2A was responsible for dephosphorylation of mitotic Plk1 in response to DNA damage. In knockdown of PP 2A catalytic subunits, Plk1 was not dephosphorylated, but rather degraded in response to DNA damage, and cells did not accumulate in G(2)-like phase. The effect of ATM/Chk1 inhibition was counteracted by overexpression of PP 2A, indicated that PP 2A may function as a downstream target of ATM/Chk1 at a mitotic DNA damage checkpoint or may have a dominant effect on ATM/Chk1 function at this checkpoint. Finally, we have shown that negative regulation of Plk1 by dephosphorylation is important to cell accumulation in G(2)-like phase at the mitotic DNA damage checkpoint, and that this ATM/Chk1/PP 2A pathway independent on p53 is a novel mechanism of cellular response to mitotic DNA damage.
机译：细胞分裂周期中的DNA损伤可以激活关卡点途径中涉及的ATM / ATR及其下游激酶，并且细胞生长停止，直到修复损伤为止。由于通过阿霉素处理在有丝分裂细胞中诱导的DNA损伤，细胞蓄积在G（2）-样阶段，而不是有丝分裂。在这些条件下，两个有丝分裂特异性激酶Cdk1和Plk1分别被抑制性磷酸化和去磷酸化抑制。 G（2）Cdc25的特异性磷酸化在有丝分裂DNA损伤后的孵育过程中增加。通过去磷酸化抑制Plk1取决于ATM / Chk1活性。使用小发夹RNA（shRNA）质粒构建体可实现ATM和Chk1的枯竭表达。在这种情况下，损坏的有丝分裂细胞没有积累在G（2）样阶段，并立即进入G（1）阶段。蛋白磷酸酶2A负责响应DNA损伤的有丝分裂Plk1的去磷酸化。在PP 2A催化亚基的敲低，Plk1没有去磷酸化，而是降解对DNA损伤的响应，并且细胞没有在G（2）样阶段积累。 PP 2A的过表达抵消了ATM / Chk1抑制作用，表明PP 2A可能在有丝分裂DNA损伤检查点作为ATM / Chk1的下游靶标，或在该检查点对ATM / Chk1的功能起主要作用。最后，我们已经表明，通过去磷酸化对Plk1进行负调控对于有丝分裂DNA损伤检查点的G（2）样相中的细胞积累非常重要，并且这种独立于p53的ATM / Chk1 / PP 2A途径是一种新的机制细胞对有丝分裂DNA损伤的反应。

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