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Matsumoto, Y. DNA-Dependent Protein Kinase in Non-Homologous End Joining. Encyclopedia. Available online: https://encyclopedia.pub/entry/22534 (accessed on 22 December 2025).
Matsumoto Y. DNA-Dependent Protein Kinase in Non-Homologous End Joining. Encyclopedia. Available at: https://encyclopedia.pub/entry/22534. Accessed December 22, 2025.
Matsumoto, Yoshihisa. "DNA-Dependent Protein Kinase in Non-Homologous End Joining" Encyclopedia, https://encyclopedia.pub/entry/22534 (accessed December 22, 2025).
Matsumoto, Y. (2022, April 30). DNA-Dependent Protein Kinase in Non-Homologous End Joining. In Encyclopedia. https://encyclopedia.pub/entry/22534
Matsumoto, Yoshihisa. "DNA-Dependent Protein Kinase in Non-Homologous End Joining." Encyclopedia. Web. 30 April, 2022.
DNA-Dependent Protein Kinase in Non-Homologous End Joining
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23084264

DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. 

DNA double-strand break (DSB) non-homologous end joining (NHEJ) DNA-dependent protein kinase (DNA-PK) phosphatidylinositol 3-kinase

1. DNA double-strand break repair

Ionizing radiation (IR) is thought to exert a variety of biological effects through the induction of damages on DNA. One Gy of X-ray or γ-ray is estimated to induce approximately 500 thymine glycols, 150 DNA-protein crosslinks, 1000 single-strand breaks, and 40 double-strand breaks (DSBs) [1]. DSB is considered the most deleterious among the various types of DNA damage.
In eukaryotes, DSB is repaired mainly through homologous recombination (HR) and non-homologous end joining (NHEJ) [2]. There are two other pathways, i.e., alternative end joining (A-EJ) and single-strand annealing (SSA) [2]. A-EJ is also termed microhomology-mediated end joining (MMEJ) or DNA polymerase theta-mediated end joining (TMEJ). These four pathways are distinguished by their usage of sequence homology (Figure 1). HR reconstitutes the DNA sequence around DSB using a homologous or identical sequence as the template, which is usually longer than 100 base pairs (bp). On the other hand, NHEJ utilizes little or no sequence homology, i.e., 0–4 bp. A-EJ and SSA utilize sequence homology of 2–20 bp and more than 50 bp, respectively. HR, A-EJ and SSA are preceded by the end resection, which creates single-stranded DNA with 3′-overhang. The end resection proceeds in two stages, i.e., initial short-range resection (≈100 nucleotides (nt)) followed by long-range resection (several hundred or thousand nt). While A-EJ requires only short-range resection, HR and SSA require long-range resection.
Figure 1. DNA double-strand break pathways. DSB: DNA double-strand break, NHEJ: non-homologous end joining, A-EJ: alternative end joining, SSA: single-strand annealing, HR: homologous recombination.
In NHEJ, the DNA ends that are not compatible for ligation undergo end processing, which results in the deletion or insertion of nucleotides at the junction. In addition, joining of the ends in close vicinity may sometimes lead to ligation of incorrect pairs of DNA ends, resulting in chromosomal aberrations such as deletions, inversions, and translocations. Thus, NHEJ is considered more error-prone than HR. However, HR in vertebrates has a requirement for the sister chromatid and is restricted to late S and G2 phases. (Note: a very recent study demonstrated that DSBs at the centromere are repaired through HR even in the G1 phase [3].) The majority of cells are in G1 and G0 phases, in which cells rely on NHEJ to repair DSBs. In human cells, NHEJ accounts for approximately 80% of DSB repair even in the G2 phase [2]. Moreover, in most cases, the deletion or insertion of a small number of nucleotides can be tolerated, because only a small portion of the genome encodes proteins. A-EJ and SSA are thought to be more error-prone than NHEJ, because they are apt to occur between repetitive sequences, resulting in the loss of the sequence in between.
NHEJ is also implicated in the process of V(D)J recombination in vertebrate immune system [2]. Enormous diversity of immunoglobulins and T cell receptors are generated through the recombination of V (variable), D (diversity), and J (joining) segments, each of which can be selected from a number of segments. Recombination activating gene 1 and 2 (RAG1 and RAG2) induce a cleavage between the selected segments and the flanking recombination signal sequences.

2. DNA-PK and Its Role NHEJ

DNA-dependent protein kinase (DNA-PK) is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku heterodimer (hereafter denoted Ku), which consists of Ku80 (also termed Ku86) and Ku70 [4][5]. DNA-PK binds to and is activated by the end of a double-stranded DNA (dsDNA). Thus, DNA-PK acts as the sensor for the end of dsDNA, which appears when a DSB is generated.
DNA-PKcs is a huge protein consisting of 4128 amino acids (Figure 2A) [6]. DNA-PKcs is structurally related to Ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, which are also implicated in DNA repair and DNA damage response [6][7][8][9]. ATM is recruited to DSB by the MRN complex consisting of Mre11, Rad50 and Nbs1, the last of which is responsible for Nijmegen breakage syndrome [10][11]. ATR is recruited to ssDNA through interaction with ATR-interacting protein (ATRIP) and Replication Protein A (RPA) [12]. These kinases show structural similarity to phosphatidylinositol 3-kinases (PI3Ks) and assemble the PIKK family. There are three additional PIKK members in humans, i.e., mammalian Target of rapamycin (mTOR, also termed FKBP12-rapamycin-associated protein, FRAP, and Rapamycin and FKBP12-target, RAFT) [13][14], Suppressor of morphological defects on genitalia-1 (SMG-1) [15][16], and Transformation/transcription domain-associated protein (TRRAP) [17]. Interestingly, TRRAP lacks kinase catalytic activity [17]. In addition to the kinase domain, these proteins share the FAT (FRAP, ATM and TRRAP), PRD (PIKK-regulatory domain) and FATC (FAT C-terminal) domains (Figure 2A). The primary function of mTOR is the regulation of cell growth and survival [13][14]. SMG-1 is essential for nonsense-mediated mRNA decay (NMD) [15][16]. PI3Ks mediates the signals from G-protein coupled receptors and receptor tyrosine kinases through the activation of AKT protein kinase (also known as protein kinase B, PKB) and mTOR [18][19][20]. This signaling pathway is called the PI3K/AKT/mTOR pathway. There are lines of evidence implicating these molecules in DNA damage response, although less directly than DNA-PKcs, ATM, and ATR [18][19][20]. SMG-1 was shown to activate the G1/S checkpoint through p53 upregulation and Cdc25A downregulation [21][22]. Recent studies showed that the human papilloma virus E6 protein and DNMT1 enhance radiosensitivity via the downregulation of SMG-1 [23][24]. The PI3K/AKT/mTOR pathway is upregulated in response to radiation and promotes cell survival [25]. AKT inhibits apoptosis through the downregulation of proapoptotic proteins, such as B cell lymphoma 2 associated agonist of cell death (BAD) [26][27] and upregulation of antiapoptotic proteins, such as human homolog of murine double minute 2 (HDM2), which promotes the degradation of p53 [28]. It is also reported that AKT augments NHEJ and HR [29][30]. Moreover, DNA-PK is shown to activate AKT in response to DNA damage directly or indirectly via Sty1/Spc1-interacting protein 1 (Sin1) [31][32]. The upregulation of the PI3K/AKT/mTOR pathway is frequently found in various types of cancer and is associated with resistance to radiotherapy and chemotherapy [18][19][20]. Thus, mTOR and PI3Ks are considered promising targets for radiosensitization and chemosensitization.
Figure 2. Structure of DNA-PK and its role in NHEJ. (A), structure of DNA-PKcs and other PIKK family members. FRAP, ATM and TRRAP (FAT) domain, PIKK-regulatory domain (PRD) and FAT C-terminal (FATC) domains are highlighted. (B), structure of Ku80 and Ku70. The von Willebrant factor A (VWA) domain, core domain, SAF-A/B, Acinus and PIAS (SAP) domain and DNA-PKcs binding motif are highlighted. (C), the structure of DNA-PKcs complexed with Ku70, Ku80 and dsDNA (RCSB PDB 7K0Y). (D), the structure of DNA-PKcs bound to ATPγS (RCSB PDB 7OTP). (E), a model for NHEJ. NHEJ proceeds in three stages, (i) the recognition stage, (ii) the processing stage and (iii) the ligation stage. DNA-PK acts in the recognition stage. Figures (A,B,E) are reproduced from the recent reviews [33][34] with some modifications. Figures (C,D) were drawn using Mol* Viewer [35].
Ku80 and Ku70 consist of 732 and 609 amino acids, respectively (Figure 2B) [36][37]. Ku was initially identified as the antigen against autoantibody in a patient with an autoimmune disease, scleroderma-polymyositis overlap syndrome. Ku binds to the end of dsDNA without any particular preference in the nucleotide sequence [38]. DNA-PKcs is recruited to the end of dsDNA via interaction with the C-terminal region of Ku80 [39].
X-ray crystallography showed that Ku forms a ring-shaped structure that can encircle DNA, accounting for how Ku binds selectively to DNA ends [40]. Recent cryoelectron microscopy (cryo-EM) studies revealed a structure of DNA-PKcs complexed with Ku and DNA [41] (Figure 2C). DNA-PKcs is folded into a ring and a head. The ring includes the HEAT repeats and the interface with Ku, while the head includes FAT, kinase, PRD, and FAT-C domains [41]. DNA is inserted into the rings of Ku and DNA-PKcs [41]. The structural differences between inactive and active states of DNA-PKcs are also revealed. Most notably, PRD is closed in the inactive state and is assumed to clash with the substrate polypeptide. However, PRD becomes open in the active state, allowing the entry of a substrate polypeptide. Another cryo-EM study revealed the structure of DNA-PKcs in a complex with adenosine-5′-(γ-thio)-triphosphate (ATPγS), which is a non-hydrolyzable ATP analog [42] (Figure 2D). The adenine group is inserted into a hydrophobic pocket surrounded by Tyr3791, Trp3805 and Leu3806 [42]. Three phosphate groups and Mg2+ ions come in contact with Asn3926, Asn3927, Asp3941, Ser3731 and Lys3753 [42]. These multiple interactions are thought to stabilize the interaction between DNA-PKcs and ATP. While Lys3753, Tyr3791, Trp3805, Asn3927 and Asp3941 are fully conserved among PIKKs, Ser3731, Leu3806 and Asn3926 are divergent. The structures of DNA-PKcs with inhibitors were also elucidated (see below).
Ku and DNA-PKcs have been shown to be essential for NHEJ (Figure 2E and for details, refer to another review [33]). Initially, Ku80 was shown to correspond to X-ray repair cross-complementing group (XRCC) 5, which is deficient in a series of rodent cell lines exhibiting hypersensitivity to IR and defective V(D)J recombination [43][44]. Subsequently, DNA-PKcs was shown to correspond to XRCC7 and to be the responsible gene for murine severe combined immunodeficiency (scid) mutation [45][46][47]. Thereafter, a number of cells and animals deficient for DNA-PKcs, Ku80 or Ku70 were found or generated through gene targeting or genome editing [33]. In addition, six human individuals that harbor homozygous or compound heterozygous mutations in DNA-PKcs have been identified [33].
NHEJ proceeds in three stages (Figure 2E). In the recognition stage, Ku first binds to the end of DNA and then recruits DNA-PKcs. Paralog of XRCC4 and XLF (PAXX) stabilizes the binding of Ku to DNA and facilitates the subsequent assembly of the NHEJ factors [47][48][49][50]. When DNA ends are not compatible, they undergo the processing stage (for details, refer to review [2]). Artemis, in a complex with DNA-PKcs, exerts endonuclease activity on hairpin and overhang structures and 5′ to 3′ exonuclease activity on single-stranded DNA [51][52]. DNA polymerase μ (Polμ) and DNA polymerase λ (Polλ) fill in the gaps in DSBs. Polynucleotide kinase phosphatase (PNKP) adds a phosphate group at the 5′-end if absent and removes the phosphate group present at the 3′-end. Aprataxin (APTX) removes adenosinemonophosphate (AMP) from the abortive intermediates of ligation. Tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 remove the covalently bound proteins and phosphoglycolate groups from 3′-ends. In the ligation stage, DNA ligase IV (LIG4), which is associated with XRCC4, joins two DNA ends together [53][54][55]. XRCC4-like factor (XLF, also known as Cernunnos) forms filaments with XRCC4, which are suggested to align or bridge two DNA ends [56][57][58].
The kinase activity of DNA-PKcs is required for NHEJ because the catalytically inactive (kinase-dead) form of DNA-PKcs cannot rescue the radiosensitivity and V(D)J recombination defects of DNA-PKcs-deficient cells [59][60]. Although the precise roles of protein phosphorylation by DNA-PKcs remain elusive, DNA-PKcs is shown to phosphorylate NHEJ factors and other potentially NHEJ-related proteins (Table 1). The significance of phosphorylation of each substrate protein has been discussed elsewhere [34]. A number of small molecules that inhibit DNA-PK have been developed to date. These compounds have been powerful tools to delineate the function of DNA-PK. Furthermore, they are promising agents in cancer therapy, sensitizing cancer cells to radiotherapy and chemotherapy.
Table 1. DNA-PK substrates and their functions.

Substrates

Function

Substrates

Function

[DNA Repair and Damage Signaling]

[Transcription]

(NHEJ)

RNA polymerase II

Transcription (general)

DNA-dependent protein kinase catalytic subunit (DNA-PKcs)

DNA-PK complex

TATA box-binding protein (TBP)

Ku autoantigen 80kDa subunit (Ku80)

p53

Transcription (specific)

Specificity protein 1 (Sp1)

Ku autoantigen 70 kDa subunit (Ku70)

c-Jun

c-Fos

DNA ligase IV (LIG4)

Ligation complex

c-Myc

X-ray repair cross-complementing group 4 (XRCC4)

Octamer-binding factor 1 (Oct-1)

XRCC4-like factor (XLF)

Serum response factor (SRF)

Artemis

Nuclease

[RNA metabolism]

Polynucleotide kinase phosphatase (PNKP)

Kinase, phosphatase

Nuclear DNA helicase II (NDHII)

Transcription and RNA processing

Werner syndrome protein (WRN)

Helicase, nuclease

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1)

RNA splicing

(Other DNA repair and damage signaling pathways)

Ataxia telangiectasia mutated (ATM)

Protein kinase; HR and cell cycle checkpoint

Heterogeneous nuclear ribonucleoprotein U (hnRNP-U)

Replication protein A 2 (RPA2)

Single-stranded DNA binding; HR and DNA replication

Fused in sarcoma (FUS)

RNA binding

Poly(ADP-ribose) polymerase 1 (PARP1)

Single-strand break repair

[Signaling]

Excision repair cross complementing 1 (ERCC1)

Nuclease component; nucleotide excision repair

Akt1

Protein kinase

Akt2

Protein kinase

[DNA replication]

Sty1/Spc1-interacting protein 1 (Sin1)

Protein kinase regulator

DNA ligase I (LIG1)

Ligation

Minichromosome maintenance 3 (MCM3)

Initiation of replication

[Organelle, cytoskeleton]

[Nucleosome and chromatin structure]

Golgi phosphoprotein 3 (GOLPH3)

Linking Golgi membrane to cytoskeleton

Histone H2AX

Core histone component; recruitment of DSB repair proteins

Vimentin

Intermediate filament

Histone H1

Linker histone

Tau

Microtubule regulation

High mobility group 1 (HMG1)

Maintenance and regulation of chromatin structure

[Protein maintenance]

High mobility group 2 (HMG2)

Heat shock protein 90 alpha (HSP90a)

Protein chaperone

C1D

Valosin-containing protein (VCP)

AAA+ ATPase

Topoisomerase I

Regulation of topological status of DNA

[Metabolism]

Topoisomerase II

Fumarate hydratase (FH)

Production of L-malate from fumarate; regulation of NHEJ

Nuclear orphan receptor 4A2 (NR4A2)

Chromatin regulation; regulation of NHEJ

    

Pituitary tumor-transforming gene (PTTG)

Regulation of chromosome segregation

    

 

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Subjects: Biochemistry & Molecular Biology
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