Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Vermillion, SD, USA.
Cell Cycle. 2013 Jul 15;12(14):2255-65. doi: 10.4161/cc.25349.
In response to DNA damage or replication stress, proliferating cells are arrested at different cell cycle stages for DNA repair by downregulating the activity of both the cyclin-dependent kinases (CDKs) and other important cell cycle kinases, including Polo-like kinase 1 (PLK1) . The signaling pathway to inhibit CDKs is relatively well understood, and breast cancer gene 1 (BRCA1) and other DNA damage response (DDR) factors play a key role in this process. However, the DNA damage-induced inhibition of PLK1 is still largely a mystery. Here we show that DNA damage and replication stress stimulate the association between BRCA1 and PLK1. Most importantly, we demonstrate that BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of Aurora A, hBora, and PLK1. Together with previous findings, we propose that in response to replication stress and DNA damage, BRCA1 plays a critical role in downregulating the kinase activity of both CDKs and PLK1.
针对 DNA 损伤或复制应激，增殖细胞通过下调细胞周期蛋白依赖性激酶 (CDKs) 和其他重要的细胞周期激酶（包括 Polo 样激酶 1 (PLK1)）的活性而在不同的细胞周期阶段停滞，以进行 DNA 修复。抑制 CDK 的信号通路相对较好理解，乳腺癌基因 1 (BRCA1) 和其他 DNA 损伤反应 (DDR) 因子在该过程中发挥关键作用。然而，DNA 损伤诱导的 PLK1 抑制在很大程度上仍是一个谜。在这里，我们表明 DNA 损伤和复制应激刺激 BRCA1 与 PLK1 之间的关联。最重要的是，我们证明 BRCA1 通过调节 Aurora A、hBora 和 PLK1 的动态相互作用来下调 PLK1 的激酶活性。结合以前的研究结果，我们提出，在应对复制应激和 DNA 损伤时，BRCA1 在下调 CDK 和 PLK1 的激酶活性方面发挥着关键作用。
