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首页> 外文期刊>Neoplasia: an international journal for oncology research >The Catalytic Subunit of DNA-Dependent Protein Kinase Coordinates with Polo-Like Kinase 1 to Facilitate Mitotic Entry
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The Catalytic Subunit of DNA-Dependent Protein Kinase Coordinates with Polo-Like Kinase 1 to Facilitate Mitotic Entry

机译：DNA依赖性蛋白激酶的催化亚基用Polo样激酶1坐标，以促进有丝分裂入口

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摘要

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the key regulator of the non-homologous end joining pathway of DNA double-strand break repair. We have previously reported that DNA-PKcs is required for maintaining chromosomal stability and mitosis progression. Our further investigations reveal that deficiency in DNA-PKcs activity caused a delay in mitotic entry due to dysregulation of cyclin-dependent kinase 1 (Cdk1), the key driving force for cell cycle progression through G2/M transition. Timely activation of Cdk1 requires polo-like kinase 1 (Plk1), which affects modulators of Cdk1. We found that DNA-PKcs physically interacts with Plk1 and could facilitate Plk1 activation both in vitro and in vivo. Further, DNA-PKcs–deficient cells are highly sensitive to Plk1 inhibitor BI2536, suggesting that the coordination between DNA-PKcs and Plk1 is not only crucial to ensure normal cell cycle progression through G2/M phases but also required for cellular resistance to mitotic stress. On the basis of the current study, it is predictable that combined inhibition of DNA-PKcs and Plk1 can be employed in cancer therapy strategy for synthetic lethality.
机译：DNA依赖性蛋白激酶催化亚基（DNA-PKC）是DNA双链断裂修复的非同源终端连接途径的关键调节剂。我们此前据报道，维持DNA-PKCs用于维持染色体稳定性和有丝分裂进展。我们的进一步调查表明，由于细胞周期蛋白依赖性激酶1（CDK1）的失调，DNA-PKCS活性的缺陷导致有丝分裂的延迟，通过G2 / M转变，细胞周期的关键驱动力。及时激活CDK1需要Polo样激酶1（PLK1），其影响CDK1的调节剂。我们发现DNA-PKCS与PLK1物理相互作用，可以促进PLK1在体外和体内激活。此外，DNA-PKCS缺陷细胞对PLK1抑制剂BI2536非常敏感，表明DNA-PKCS和PLK1之间的协调不仅至关重要，不能通过G2 / M阶段来确保正常细胞周期进展，而是对有丝分裂的细胞抗性所需的细胞抗性。在目前的研究的基础上，可以预测DNA-PKC和PLK1的结合抑制可用于癌症治疗策略的合成致死性。

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