DNA-PKcs: A Multi-Faceted Player in DNA Damage Response

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.

High Expression of Cancer-IgG Is Associated With Poor Prognosis and Radioresistance via PI3K/AKT/DNA-PKcs Pathway Regulation in Lung Adenocarcinoma

“…However, the expression of p-AKT and p-GSK3β decreased; this result was consistent with that of the phosphorylation protein microarray analysis. p-DNA-PKcs, a core component in the NHEJ pathway for the DSB damage repair process, is phosphorylated under cellular stress and assembled into DNA-PK with Ku70 and Ku80 heterodimers to participate in the repair process of DSBs; they also cascade to amplify repair signals and recruit more sensor proteins to repair sites to promote repair ( 25 ). The results showed that expression of the p-DNA-PKcs protein in LUAD cells increased after radiation.…”

The Role of DNA Damage Response in Dysbiosis-Induced Colorectal Cancer

“…ATM phosphorylates several proteins that will mediate cell cycle arrest and DNA repair [25]. In this sense, DNA-PK and H2AX histone are phosphorylated and hence activated by ATM [29]. Phosphorylated H2AX (γ-H2AX) will recruit more ATM molecules together with DNA repair factors [25].…”

Structural insights into the role of DNA-PK as a master regulator in NHEJ

“…1). DNA-PKcs interacts with Ku70/80 in the presence of dsDNA to form the active DNA-dependent protein kinase holoenzyme DNA-PK, and is required for non-homologous end joining (NHEJ), the major pathway for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) in human cells (Yue et al, 2020;Zhao et al, 2020a). In NHEJ, the Ku heterodimer binds directly to DSB ends (Fig.…”

“…DNA-PKcs and Artemis are also required for opening DNA hairpin coding ends during V(D)J recombination and cells lacking DNA-PKcs, Ku, XRCC4 or DNA ligase IV are radiation sensitive and defective in NHEJ and V(D)J recombination (Pannunzio et al, 2018). Recently, additional roles for DNA-PKcs, outside DSB repair have been reported (Yue et al, 2020), including mitosis (Douglas et al, 2014(Douglas et al, , 2020Jette & Lees-Miller, 2015;Lee et al, 2011), transcription (Goodwin et al, 2015;Ju et al, 2006), RNA processing (Shao et al, 2020), metastasis (Goodwin et al, 2015), metabolism (Chung, 2018;Park et al, 2017), the innate immune response (Yang et al, 2020) and HIV replication (Anisenko et al, 2020), but its most well-characterized role is in NHEJ.…”