PDF(Pubmed)
Abstract：
The DNA-dependent protein kinase (DNA-PK), catalytic subunit, also known as DNA-PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA-PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA-PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA-PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS-STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA-PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA-PKcs and diseases for better targeting DNA-PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA-PKcs in human diseases, meanwhile, we discuss the progresses of DNA-PKcs inhibitors and their potential in clinical trials. The most updated review about DNA-PKcs will hopefully provide insights and ideas to understand DNA-PKcs associated diseases.
摘要：
DNA依赖性蛋白激酶(DNA-PK),催化亚基，也被称为DNA-PKcs，与异二聚体Ku70/Ku80复合形成DNA-PK全酶，在双链断裂（DSB）后的非同源末端连接（NHEJ）修复中被公认为起始物。在NHEJ期间，DNA-PKcs对于DNA末端加工和末端连接都是必需的。除了其在DSB修复中的经典功能外，DNA-PKcs还在各种生物活性中显示出多方面的功能，例如B/T淋巴细胞发育中的类别转换重组（CSR）和可变（V）多样性（D）连接（J）重组，通过cGAS-STING途径的先天免疫，转录,交替拼接,等等，这取决于它在NHEJ中的功能。此外，DNA-PKcs缺乏已被证明与人类疾病如神经系统发病机制有关,癌症,免疫疾病，等等通过不同的机制。因此,必须总结有关DNA-PKcs和疾病的最新发现，以更好地靶向DNA-PKcs，在临床前模型中已显示出在癌症治疗中的功效。这里,我们讨论了DNA-PKcs在人类疾病中的多方面作用，同时,我们讨论了DNA-PKcs抑制剂的进展及其在临床试验中的潜力。关于DNA-PKcs的最新评论有望为理解DNA-PKcs相关疾病提供见解和思路。
