PDF(Pubmed)
Abstract：
Although DNA-PK inhibitors (DNA-PK-i) have been applied in clinical trials for cancer treatment, the biomarkers and mechanism of action of DNA-PK-i in tumor cell suppression remain unclear. Here, we observed that a low dose of DNA-PK-i and PARP inhibitor (PARP-i) synthetically suppresses BRCA-deficient tumor cells without inducing DNA double-strand breaks (DSBs). Instead, we found that a fraction of DNA-PK localized inside of nucleoli, where we did not observe obvious DSBs. Moreover, the Ku proteins recognize pre-rRNA that facilitates DNA-PKcs autophosphorylation independent of DNA damage. Ribosomal proteins are also phosphorylated by DNA-PK, which regulates pre-rRNA biogenesis. In addition, DNA-PK-i acts together with PARP-i to suppress pre-rRNA biogenesis and tumor cell growth. Collectively, our studies reveal a DNA damage repair-independent role of DNA-PK-i in tumor suppression.
摘要：
尽管DNA-PK抑制剂（DNA-PK-i）已用于癌症治疗的临床试验，DNA-PK-i在肿瘤细胞抑制中的生物标志物和作用机制尚不清楚.这里,我们观察到,低剂量的DNA-PK-i和PARP抑制剂(PARP-i)可合成抑制BRCA缺陷型肿瘤细胞,而不诱导DNA双链断裂(DSB).相反，我们发现一部分DNA-PK位于核仁内部,我们没有观察到明显的DSB。此外，Ku蛋白识别pre-rRNA,其促进DNA-PKcs自磷酸化而不依赖于DNA损伤。核糖体蛋白也被DNA-PK磷酸化，调节前rRNA生物发生。此外,DNA-PK-i与PARP-i一起作用以抑制前rRNA生物发生和肿瘤细胞生长。总的来说，我们的研究揭示了DNA-PK-i在肿瘤抑制中的DNA损伤修复非依赖性作用.
