Abstract
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related kinase family, which can phosphorylate more than 700 substrates. As the core enzyme, DNA-PKcs forms the active DNA-PK holoenzyme with the Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once DNA double strand breaks (DSBs) occur in the cells, DNA-PKcs is promptly recruited into damage sites and activated. DNA-PKcs is auto-phosphorylated and phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, and phosphorylates other targets, participating in a series of DDR and repair processes, which determine the cells’ fates: DSBs NHEJ repair and pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due to the special and multi-faceted roles of DNA-PKcs in the cellular responses to DNA damage, it is important to precisely regulate the formation and dynamic of its functional complex and activities for guarding genomic stability. On the other hand, targeting DNA-PKcs has been considered as a promising strategy of exploring novel radiosensitizers and killing agents of cancer cells. Combining DNA-PKcs inhibitors with radiotherapy can effectively enhance the efficacy of radiotherapy, offering more possibilities for cancer therapy.
Highlights
Eukaryotic cells are constantly encountering various endogenous (e.g., DNA replication errors) and exogenous stresses of genomic DNA damage (Jeggo et al, 2016)
Considering the special role of DNA-PKcs in the DNA damage response (DDR), we have reviewed the progress on exploration of DNA-PKcs inhibitors as radiosensitizers for cancer radiotherapy
DNA-dependent protein kinase catalytic subunit belongs to the phosphatidylinositol 3kinase related kinase (PIKK) family, and is a type of DNA-activated serine/threonine protein kinase with a molecular weight of approximately 469 kD encoded by the PRKDC or XRCC7 gene (Hartley et al, 1995; Sipley et al, 1995; Lees-Miller, 1996)
Summary
Eukaryotic cells are constantly encountering various endogenous (e.g., DNA replication errors) and exogenous (ionizing radiation, chemical carcinogens, and UV) stresses of genomic DNA damage (Jeggo et al, 2016). DNA-dependent protein kinase catalytic subunit belongs to the PIKKs family, and is a type of DNA-activated serine/threonine protein kinase with a molecular weight of approximately 469 kD encoded by the PRKDC or XRCC7 gene (Hartley et al, 1995; Sipley et al, 1995; Lees-Miller, 1996). The current model suggests that DNA-PKcs S2056 phosphorylation causes conformational changes, thereby promoting DNA-PK disassembly from the DSB site, allowing DNA end ligation (Jiang et al, 2015), while the ABCDE cluster phosphorylation is required for DNA end resection (Shibata et al, 2011) Another autophosphorylation site, T3950, is located in the kinase domain and its phosphorylation was suggested to shut down the activity of DNA-PKcs kinase (Douglas et al, 2007). Proteomics showed that at least 16 lysine residues were acetylated in the DNA-PKcs
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