DNA-PK

DNA-PK

The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK-mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, further underscoring the importance of understanding its role in disease. Herein, the molecular and cellular consequences of DNA-PK are considered, with an eye toward discerning the rationale for therapeutic targeting of DNA-PK.

An overview of DNA-PK

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase activated by double-stranded DNA. DNA-PK is comprised of the p470 kDa DNA-PK catalytic subunit (DNA-PKcs) and the Ku heterodimer consisting of the p86 (Ku 80) and p70 (Ku 70) subunits. DNA-PK is a key enzyme in the repair of DNA damage in mammalian cells. They determine the outcome of damaged tumor cells. In addition, DNA-PK is involved in the direct recognition of DNA damage and plays an important role in DNA double strand break (DSB) repair, gene recombination, gene transcription, and gene regulation. DNA-PK is the most important component of the DNA non-homologous end-joining (NHEJ) repair system and a key enzyme in this process. It is involved in the repair of cellular DSB and can be widely involved in transcriptional and apoptotic processes by phosphorylating multiple protein substrates. It is important in maintaining the genetic stability of cells.

The inhibition of DNA-PK

In-depth study of DNA-PK may provide an effective molecular target for tumor sensitization and drug resistance reversal. DNA-PK inhibitors can effectively inhibit their expression, but due to the large amount and physiologically intolerable property it cannot be used for in vivo study. For example, the targeted inhibitor and Wortmannin.

DNA-PK and diseases

DNA-PK is highly expressed in various tumor tissues such as nasopharyngeal carcinoma, breast cancer, bladder cancer, and colorectal cancer. DNA-PK activity and protein expression were higher in metastatic tumors than in primary tumor cells, and DNA-PK were presumed to be involved in tumor metastasis. In vitro studies have shown that inhibition of DNA-PK expression not only leads to a decrease in tumor cell proliferation activity, but also enhances the sensitivity of tumor cells to radiation and chemotherapy drugs. Besides, DNA-PK repairs DSB caused by ionizing radiation, and the activation process requires protein phosphatase 6, which is inhibited by DNA-PK.

References:

Chung, J. H. (2018) The role of DNA-PK in aging and energy metabolism. FEBS Journal, 285: 1959–1972.

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