The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases

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.

Keywords

class switch recombination / DNA damage / DNA-PKcs / innate immunity / V(D)J recombination

References

1	PA Jeggo, LH Pearl, AM Carr. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer. 2016;16(1):35-42.
2	SP Jackson, J Bartek. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071-1078.
3	R-X Huang, P-K Zhou. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther. 2020;5(1):60.
4	MR Lieber. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008;283(1):1-5.
5	KK Chiruvella, Z Liang, TE Wilson. Repair of double-strand breaks by end joining. Cold Spring Harb Perspect Biol. 2013;5(5):a012757.
6	HHY Chang, NR Pannunzio, N Adachi, MR Lieber. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18(8):495-506.
7	A Shibata, PA Jeggo. Canonical DNA non-homologous end-joining; capacity versus fidelity. Br J Radiol. 2020;93(1115):20190966.
8	E Dylgjeri, KE Knudsen. DNA-PKcs: a targetable protumorigenic protein kinase. Cancer Res. 2022;82(4):523-533.
9	L Liu, Y Deng, Z Zheng, et al. Hsp90 inhibitor STA9090 sensitizes hepatocellular carcinoma to hyperthermia-induced DNA damage by suppressing DNA-PKcs protein stability and mRNA transcription. Mol Cancer Ther. 2021;20(10):1880-1892.
10	T Carter, I Vancurová, I Sun, W Lou, S DeLeon. A DNA-activated protein kinase from HeLa cell nuclei. Mol Cell Biol. 1990;10(12):6460-6471.
11	S Bergstrand, EM O'Brien, C Coucoravas, et al. Small Cajal body-associated RNA 2 (scaRNA2) regulates DNA repair pathway choice by inhibiting DNA-PK. Nat Commun. 2022;13(1):1015.
12	R Bosotti, A Isacchi, EL Sonnhammer. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci. 2000;25(5):225-227.
13	AN Blackford, SP Jackson. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66(6):801-817.
14	Z Shao, AJ Davis, KR Fattah, et al. Persistently bound Ku at DNA ends attenuates DNA end resection and homologous recombination. DNA Repair (Amst). 2012;11(3):310-316.
15	X Chi, Y Li, X Qiu. V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation. Immunology. 2020;160(3):233-247.
16	JL Crowe, Z Shao, XS Wang, et al. Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination. Proc Natl Acad Sci USA. 2018;115(34):8615-8620.
17	JL Crowe, XS Wang, Z Shao, BJ Lee, VM Estes, S Zha. DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination. Proc Natl Acad Sci USA. 2020;117(37):22953-22961.
18	KT Tan, CN Yeh, YC Chang, et al. PRKDC: new biomarker and drug target for checkpoint blockade immunotherapy. J Immunother Cancer. 2020;8(1).
19	Y Chen, Y Li, Y Guan, et al. Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors. Mol Oncol. 2020;14(9):2096-2110.
20	KK Leuther, O Hammarsten, RD Kornberg, G Chu. Structure of DNA-dependent protein kinase: implications for its regulation by DNA. Embo j. 1999;18(5):1114-1123.
21	Y Ma, U Pannicke, K Schwarz, MR Lieber. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002;108(6):781-794.
22	DW Chan, BP Chen, S Prithivirajsingh, et al. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev. 2002;16(18):2333-2338.
23	L Spagnolo, A Rivera-Calzada, LH Pearl, O Llorca. Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell. 2006;22(4):511-519.
24	BL Sibanda, DY Chirgadze, TL Blundell. Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature. 2010;463(7277):118-121.
25	X Yin, M Liu, Y Tian, J Wang, Y Xu. Cryo-EM structure of human DNA-PK holoenzyme. Cell Res. 2017;27(11):1341-1350.
26	H Sharif, Y Li, Y Dong, et al. Cryo-EM structure of the DNA-PK holoenzyme. Proc Natl Acad Sci USA. 2017;114(28):7367-7372.
27	S Liang, SE Thomas, AK Chaplin, SW Hardwick, DY Chirgadze, TL Blundell. Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs. Nature. 2022;601(7894):643-648.
28	R Ceccaldi, B Rondinelli, AD D'Andrea. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2016;26(1):52-64.
29	Z Guo, S Wang, Y Xie, et al. HUWE1-dependent DNA-PKcs neddylation modulates its autophosphorylation in DNA damage response. Cell Death Dis. 2020;11(5):400.
30	CJ Buehl, NJ Goff, SW Hardwick, et al. Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining. Mol Cell. 2023;83(5):698-714.e4.
31	L Liu, X Chen, J Li, et al. Autophosphorylation transforms DNA-PK from protecting to processing DNA ends. Mol Cell. 2022;82(1):177-189.e4.
32	Y Zhu, W Jiang, BJ Lee, A Li, S Gershik, S Zha. Phosphorylation of DNA-PKcs at the S2056 cluster ensures efficient and productive lymphocyte development in XLF-deficient mice. Proc Natl Acad Sci USA. 2023;120(25):e2221894120.
33	X Chen, X Xu, Y Chen, et al. Structure of an activated DNA-PK and its implications for NHEJ. Mol Cell. 2021;81(4):801-810 e3.
34	WM Chen, JC Chiang, Z Shang, et al. DNA-PKcs and ATM modulate mitochondrial ADP-ATP exchange as an oxidative stress checkpoint mechanism. Embo j. 2023;42(6):e112094.
35	G Watanabe, MR Lieber. Dynamics of the artemis and DNA-PKcs complex in the repair of double-strand breaks. J Mol Biol. 2022;434(23):167858.
36	W Jiang, JL Crowe, X Liu, et al. Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining. Mol Cell. 2015;58(1):172-185.
37	H Lu, Q Zhang, DJ Laverty, et al. ATM phosphorylates the FATC domain of DNA-PKcs at threonine 4102 to promote non-homologous end joining. Nucleic Acids Res. 2023;51(13):6770-6783.
38	Y Ma, U Pannicke, H Lu, D Niewolik, K Schwarz, MR Lieber. The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. J Biol Chem. 2005;280(40):33839-33846.
39	Y Zhou, TT Paull. DNA-dependent protein kinase regulates DNA end resection in concert with Mre11-Rad50-Nbs1 (MRN) and ataxia telangiectasia-mutated (ATM). J Biol Chem. 2013;288(52):37112-37125.
40	F Lafont, F Fleury, H Benhelli-Mokrani. DNA-PKcs Ser2056 auto-phosphorylation is affected by an O-GlcNAcylation/phosphorylation interplay. Biochim Biophys Acta. 2020;1864(12):129705.
41	AJ Davis, L Chi, S So, et al. BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle. Nucleic Acids Res. 2014;42(18):11487-11501.
42	Y Xie, Y-K Liu, Z-P Guo, et al. RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase. Cell Death Differ. 2020;27(4):1383-1397.
43	X Jiang, Y Sun, S Chen, K Roy, BD Price. The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM. J Biol Chem. 2006;281(23):15741-15746.
44	P Javvadi, H Makino, AK Das, et al. Threonine 2609 phosphorylation of the DNA-dependent protein kinase is a critical prerequisite for epidermal growth factor receptor-mediated radiation resistance. Mol Cancer Res. 2012;10(10):1359-1368.
45	G Liccardi, JA Hartley, D Hochhauser. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 2011;71(3):1103-1114.
46	P Douglas, J Zhong, R Ye, GBG Moorhead, X Xu, SP Lees-Miller. Protein phosphatase 6 interacts with the DNA-dependent protein kinase catalytic subunit and dephosphorylates gamma-H2AX. Mol Cell Biol. 2010;30(6):1368-1381.
47	S Zhu, LA Fisher, T Bessho, A Peng. Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining. Nucleic Acids Res. 2017;45(18):10583-10594.
48	PE Head, P Kapoor-Vazirani, GP Nagaraju, et al. DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining. Nucleic Acids Res. 2023;51(15):7972-7987.
49	Y-F Lin, H-Y Shih, Z Shang, S Matsunaga, BP Chen. DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response. Nucleic Acids Res. 2014;42(7):4463-4473.
50	Y-F Lin, H-Y Shih, Z-F Shang, et al. PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway. Nucleic Acids Res. 2018;46(4):1847-1859.
51	AA Patel, F Ginhoux, S Yona. Monocytes, macrophages, dendritic cells and neutrophils: an update on lifespan kinetics in health and disease. Immunology. 2021;163(3):250-261.
52	L Bird. Innate immunity: SENSING bacterial messages. Nat Rev Immunol. 2018;18(2):78.
53	D Niewolik, K Schwarz. Physical ARTEMIS:DNA-PKcs interaction is necessary for V(D)J recombination. Nucleic Acids Res. 2022;50(4):2096-2110.
54	YR Lee, GS Kang, T Oh, HJ Jo, HJ Park, GO Ahn. DNA-dependent protein kinase catalytic subunit (DNA-PKcs): beyond the DNA double-strand break repair. Mol Cells. 2023;46(4):200-205.
55	S Esenboga, C Akal, B Karaatmaca, et al. Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature. Clin Immunol. 2018;197:1-5.
56	X Sun, T Liu, J Zhao, et al. DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity. Nat Commun. 2020;11(1):6182.
57	DO Patricio, GBM Dias, LW Granella, et al. DNA-PKcs restricts Zika virus spreading and is required for effective antiviral response. Front Immunol. 2022;13:1042463.
58	ME DeWane, R Waldman, J Lu. Dermatomyositis: Clinical features and pathogenesis. J Am Acad Dermatol. 2020;82(2):267-281.
59	D Jahantigh, S Salimi, M Mousavi, et al. Association between functional polymorphisms of DNA double-strand breaks in repair genes XRCC5, XRCC6 and XRCC7 with the risk of systemic lupus erythematosus in South East Iran. DNA Cell Biol. 2015;34(5):360-366.
60	AL Mathieu, E Verronese, GI Rice, et al. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. J Allergy Clin Immunol. 2015;135(6):1578-1588 e5.
61	C Sordet, J Goetz, J Sibilia. Contribution of autoantibodies to the diagnosis and nosology of inflammatory muscle disease. Joint Bone Spine. 2006;73(6):646-654.
62	M van der Burg, H Ijspeert, NS Verkaik, et al. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest. 2009;119(1):91-98.
63	L Woodbine, JA Neal, NK Sasi, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J Clin Invest. 2013;123(7):2969-2980.
64	Y Matsumoto, A Asa, C Modak, M Shimada. DNA-dependent protein kinase catalytic subunit: the sensor for DNA double-strand breaks structurally and functionally related to ataxia telangiectasia mutated. Genes (Basel). 2021;12(8):1143.
65	C Taffoni, J Marines, H Chamma, et al. DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma. Embo j. 2023;42(7):e111961.
66	H Tsuchiya, M Shimada, K Tsukada, Q Meng, J Kobayashi, Y Matsumoto. Diminished or inversed dose-rate effect on clonogenic ability in Ku-deficient rodent cells. J Radiat Res. 2021;62(2):198-205.
67	M Tang, G Chen, B Tu, et al. SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity. Sci Adv. 2023;9(24):eade6624.
68	Y Wang, Z Fu, X Li, et al. Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation. Immunity. 2021;54(4):632-647 e9.
69	AJ Hartlerode, MJ Morgan, Y Wu, J Buis, DO Ferguson. Recruitment and activation of the ATM kinase in the absence of DNA-damage sensors. Nat Struct Mol Biol. 2015;22(9):736-743.
70	A Anisenko, A Nefedova, Y Agapkina, M Gottikh. Both ATM and DNA-PK are the main regulators of HIV-1 post-integrational DNA repair. Int J Mol Sci. 2023;24(3).
71	S Song, Y Lu, YK Choi, et al. DNA-dependent PK inhibits adeno-associated virus DNA integration. Proc Natl Acad Sci USA. 2004;101(7):2112-2116.
72	A Zahid, H Ismail, B Li, T Jin. Molecular and structural basis of DNA sensors in antiviral innate immunity. Front Immunol. 2020;11:613039.
73	S Balan, M Saxena, N Bhardwaj. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019;348:1-68.
74	C Ma, M Muranyi, CH Chu, J Zhang, WM Chu. Involvement of DNA-PKcs in the IL-6 and IL-12 response to CpG-ODN is mediated by its interaction with TRAF6 in dendritic cells. PLoS One. 2013;8(3):e58072.
75	C Ma, NP Spies, T Gong, CX Jones, WM Chu. Involvement of DNA-PKcs in the type I IFN response to CpG-ODNs in conventional dendritic cells in TLR9-dependent or -independent manners. PLoS One. 2015;10(3):e0121371.
76	G Esposito, G Palumbo, G Carillio, et al. Immunotherapy in small cell lung cancer. Cancers (Basel). 2020;12(9):2522.
77	F Wang, M Zhao, B Chang, et al. Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS. Mol Cell. 2022;82(11):2032-2049 e7.
78	A Mishra, AL Brown, X Yao, et al. Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase. Nat Commun. 2015;6:6224.
79	SY Wu, T Fu, YZ Jiang, ZM Shao. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020;19(1):120.
80	A Crinier, E Narni-Mancinelli, S Ugolini, E Vivier. SnapShot: Natural killer cells. Cell. 2020;180(6):1280-1280.e1.
81	AJ Morales, JA Carrero, PJ Hung, et al. A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages. eLife. 2017;6.
82	L Zhao, B Purandare, J Zhang, BM Hantash. beta2-Microglobulin-free HLA-G activates natural killer cells by increasing cytotoxicity and proinflammatory cytokine production. Hum Immunol. 2013;74(4):417-424.
83	T Mashimo, A Takizawa, J Kobayashi, et al. Generation and characterization of severe combined immunodeficiency rats. Cell Rep. 2012;2(3):685-694.
84	S Rajagopalan, EO Long. KIR2DL4 (CD158d): an activation receptor for HLA-G. Front Immunol. 2012;3:258.
85	M Morita, G Stamp, P Robins, et al. Gene-targeted mice lacking the Trex1 (DNase III) 3'→5' DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol. 2004;24(15):6719-6727.
86	S Rajagopalan, EO Long. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc Natl Acad Sci USA. 2012;109(50):20596-20601.
87	T Lazarov, S Juarez-Carre?o, N Cox, F Geissmann. Physiology and diseases of tissue-resident macrophages. Nature. 2023;618(7966):698-707.
88	AM Dragoi, X Fu, S Ivanov, et al. DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA. EMBO J. 2005;24(4):779-789.
89	K Hazeki, Y Kametani, H Murakami, et al. Phosphoinositide 3-kinasegamma controls the intracellular localization of CpG to limit DNA-PKcs-dependent IL-10 production in macrophages. PLoS One. 2011;6(10):e26836.
90	J Wu, W Zhu, H Fu, et al. DNA-PKcs interacts with Aire and regulates the expression of toll-like receptors in RAW264.7 cells. Scand J Immunol. 2012;75(5):479-488.
91	Z Shao, RA Flynn, JL Crowe, et al. DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis. Nature. 2020;579(7798):291-296.
92	LM Sholl. Biomarkers of response to checkpoint inhibitors beyond PD-L1 in lung cancer. Mod Pathol. 2022;35(Suppl 1):66-74.
93	J-J Meijer, A Leonetti, G Airò, et al. Small cell lung cancer: novel treatments beyond immunotherapy. Semin Cancer Biol. 2022;86(Pt 2):376-385.
94	J Wang, L Kang, D Song, et al. Ku70 senses HTLV-1 DNA and modulates HTLV-1 replication. J Immunol. 2017;199(7):2475-2482.
95	BD Gerlach, PB Ampomah, A, Yurdagul, et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab. 2021;33(12):2445-2463 e8.
96	FVS Castanheira, P Kubes. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178-2185.
97	C Silvestre-Roig, Q Braster, A Ortega-Gomez, O Soehnlein. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol. 2020;17(6):327-340.
98	ME Shaul, ZG Fridlender. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16(10):601-620.
99	T Fang, Y Zhang, VY Chang, et al. Epidermal growth factor receptor-dependent DNA repair promotes murine and human hematopoietic regeneration. Blood. 2020;136(4):441-454.
100	K Felgentreff, L Du, KG Weinacht, et al. Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells. Proc Natl Acad Sci USA. 2014;111(24):8889-8894.
101	D Gao, T Li, XD Li, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci USA. 2015;112(42):E5699-E5705.
102	Y Xiao, M Cong, J Li, et al. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. Cancer Cell. 2021;39(3):423-437 e7.
103	A Aponte-Lopez, S Munoz-Cruz. Mast cells in the tumor microenvironment. Adv Exp Med Biol. 2020;1273:159-173.
104	K Nagata, C Nishiyama. IL-10 in mast cell-mediated immune responses: anti-inflammatory and proinflammatory roles. Int J Mol Sci. 2021;22(9).
105	N Yan, AD Regalado-Magdos, B Stiggelbout, MA Lee-Kirsch, J Lieberman. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol. 2010;11(11):1005-1013.
106	DEA Komi, K Khomtchouk, PL Santa Maria. A review of the contribution of mast cells in wound healing: involved molecular and cellular mechanisms. Clin Rev Allergy Immunol. 2020;58(3):298-312.
107	T Derakhshan, JA Boyce, DF Dwyer. Defining mast cell differentiation and heterogeneity through single-cell transcriptomics analysis. J Allergy Clin Immunol. 2022;150(4):739-747.
108	P Conti, C D'Ovidio, C Conti, et al. Progression in migraine: role of mast cells and pro-inflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87-94.
109	D Ribatti. Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. Immunol Lett. 2013;152(2):83-88.
110	D Ribatti, T Annese, R Tamma. Controversial role of mast cells in breast cancer tumor progression and angiogenesis. Clin Breast Cancer. 2021;21(6):486-491.
111	Y Liu, L Zhang, Y Liu, et al. DNA-PKcs deficiency inhibits glioblastoma cell-derived angiogenesis after ionizing radiation. J Cell Physiol. 2015;230(5):1094-1103.
112	RX Huang, PK Zhou. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther. 2020;5(1):60.
113	DA Chistiakov, AN Orekhov, YV Bobryshev. Immune-inflammatory responses in atherosclerosis: role of an adaptive immunity mainly driven by T and B cells. Immunobiology. 2016;221(9):1014-1033.
114	MD Cooper, J Miller. Discovery of 2 distinctive lineages of lymphocytes, T cells and B cells, as the basis of the adaptive immune system and immunologic function: 2019 Albert Lasker Basic Medical Research Award. JAMA. 2019;322(13):1247-1248.
115	ZJ Waldrip, L Burdine, DK Harrison, et al. DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells. J Biol Chem. 2021;297(4):101209.
116	X Liu, X Cen, R Wu, et al. ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade. Nat Commun. 2023;14(1):4066.
117	M Sajish, Q Zhou, S Kishi, et al. Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-gamma and p53 signaling. Nat Chem Biol. 2012;8(6):547-554.
118	S Scarpaci, D Frasca, P Barattini, L Guidi, G Doria. DNA damage recognition and repair capacities in human naive and memory T cells from peripheral blood of young and elderly subjects. Mech Ageing Dev. 2003;124(4):517-524.
119	J Cao, G Lin, Y Gong, et al. DNA-PKcs, a novel functional target of acriflavine, mediates acriflavine's p53-dependent synergistic anti-tumor efficiency with melphalan. Cancer Lett. 2016;383(1):115-124.
120	X Yue, C Bai, D Xie, T Ma, PK Zhou. DNA-PKcs: a multi-faceted player in DNA damage response. Front Genet. 2020;11:607428.
121	S Luo, R Qiao, X Zhang. DNA damage response and repair in adaptive immunity. Front Cell Dev Biol. 2022;10:884873.
122	SM Christie, C Fijen, E Rothenberg. V(D)J recombination: recent insights in formation of the recombinase complex and recruitment of DNA repair machinery. Front Cell Dev Biol. 2022;10:886718.
123	FW Alt, Y Zhang, FL Meng, C Guo, B Schwer. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell. 2013;152(3):417-429.
124	JS Haring, X Jing, J Bollenbacher-Reilley, H-H Xue, WJ Leonard, JT Harty. Constitutive expression of IL-7 receptor alpha does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J Immun (Baltimore, Md : 1950). 2008;180(5):2855-2862.
125	M Greaves. Author Correction: A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer. 2018;18(8):526.
126	CL Hsieh, CY Okitsu, MR Lieber. Temporally uncoupled signal and coding joint formation in human V(D)J recombination. Mol Immunol. 2020;128:227-234.
127	CM Kirkham, JNF Scott, X Wang, et al. Cut-and-run: a distinct mechanism by which V(D)J recombination causes genome instability. Mol Cell. 2019;74(3):584-597.e9.
128	W Barchet, T Zillinger. Exonuclease TREX1 also Has a Sweet Tooth. Immunity. 2015;43(3):411-413.
129	MR Lieber, Y Ma, U Pannicke, K Schwarz. The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst). 2004;3(8-9):817-826.
130	EJ Gapud, BP Sleckman. Unique and redundant functions of ATM and DNA-PKcs during V(D)J recombination. Cell Cycle. 2011;10(12):1928-1935.
131	A Bj?rkman, L Du, K Felgentreff, et al. DNA-PKcs is involved in Ig class switch recombination in human B cells. J Immunol. 2015;195(12):5608-5615.
132	G Li, FW Alt, HL Cheng, et al. Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell. 2008;31(5):631-640.
133	T Uziel, Y Lerenthal, L Moyal, Y Andegeko, L Mittelman, Y Shiloh. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 2003;22(20):5612-5621.
134	T Blunt, NJ Finnie, GE Taccioli, et al. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell. 1995;80(5):813-23.
135	EJ Gapud, Y Dorsett, B Yin, et al. Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation. Proc Natl Acad Sci USA. 2011;108(5):2022-2027.
136	A Shibata, D Moiani, AS Arvai, et al. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell. 2014;53(1):7-18.
137	Z Anne Esguerra, G Watanabe, CY Okitsu, CL Hsieh, MR Lieber. DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination. Mol Immunol. 2020;120:93-100.
138	IA Rodriguez-Brenes, CS Peskin. Quantitative theory of telomere length regulation and cellular senescence. Proc Nat Acad Sci USA. 2010;107(12):5387-5392.
139	Y Li, JJ Goronzy, CM Weyand. DNA damage, metabolism and aging in pro-inflammatory T cells: rheumatoid arthritis as a model system. Exp Gerontol. 2018;105:118-127.
140	NI Dmitrieva, D Malide, MB Burg. Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA. Am J Physiol Regul Integr Comp Physiol. 2011;301(3):R632-R640.
141	J Niraj, A F?rkkil?, AD D'Andrea. The Fanconi anemia pathway in cancer. Annu Rev Cancer Biol. 2019;3:457-478.
142	B Ruis, A Molan, T Takasugi, EA Hendrickson. Absence of XRCC4 and its paralogs in human cells reveal differences in outcomes for DNA repair and V(D)J recombination. DNA Repair (Amst). 2020;85:102738.
143	C Touvrey, C Couedel, P Soulas, et al. Distinct effects of DNA-PKcs and Artemis inactivation on signal joint formation in vivo. Mol Immunol. 2008;45(12):3383-3391.
144	JM Zaretsky, A Garcia-Diaz, DS Shin, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-829.
145	YG Wang, C Nnakwe, WS Lane, M Modesti, KM Frank. Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. J Biol Chem. 2004;279(36):37282-37290.
146	S Roy, SN Andres, A Vergnes, et al. XRCC4's interaction with XLF is required for coding (but not signal) end joining. Nucleic Acids Res. 2012;40(4):1684-1694.
147	KD Klonowski, KJ Williams, AL Marzo, L Lefran?ois. Cutting edge: IL-7-independent regulation of IL-7 receptor alpha expression and memory CD8 T cell development. J Immun (Baltimore, Md : 1950). 2006;177(7):4247-4251.
148	S Liang, AK Chaplin, AK Stavridi, R Appleby, A Hnizda, TL Blundell. Stages, scaffolds and strings in the spatial organisation of non-homologous end joining: Insights from X-ray diffraction and Cryo-EM. Prog Biophys Mol Biol. 2021;163:60-73.
149	K Yu, MR Lieber. Nucleic acid structures and enzymes in the immunoglobulin class switch recombination mechanism. DNA Repair (Amst). 2003;2(11):1163-1174.
150	J Chaudhuri, FW Alt. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol. 2004;4(7):541-552.
151	K Yu, MR Lieber. Current insights into the mechanism of mammalian immunoglobulin class switch recombination. Crit Rev Biochem Mol Biol. 2019;54(4):333-351.
152	S Franco, MM Murphy, G Li, T Borjeson, C Boboila, FW Alt. DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination. J Exp Med. 2008;205(3):557-564.
153	S Rooney, FW Alt, J Sekiguchi, JP Manis. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc Natl Acad Sci USA. 2005;102(7):2471-2475.
154	A Bjorkman, L Du, K Felgentreff, et al. DNA-PKcs is involved in Ig class switch recombination in human B cells. J Immunol. 2015;195(12):5608-5615.
155	E Callen, M Jankovic, N Wong, et al. Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes. Mol Cell. 2009;34(3):285-297.
156	GC Bosma, J Kim, T Urich, et al. DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J Exp Med. 2002;196(11):1483-1495.
157	S Wang, X Wang, J Sun, et al. Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1. Int J Oral Sci. 2023;15(1):17.
158	KP Hopfner, A Karcher, L Craig, TT Woo, JP Carney, JA Tainer. Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell. 2001;105(4):473-485.
159	M Lebel. Werner syndrome: genetic and molecular basis of a premature aging disorder. Cell Mol Life Sci. 2001;58(7):857-867.
160	JP Carney, RS Maser, H Olivares, et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. 1998;93(3):477-486.
161	H Nagasawa, JB Little, YF Lin, et al. Differential role of DNA-PKcs phosphorylations and kinase activity in radiosensitivity and chromosomal instability. Radiat Res. 2011;175(1):83-89.
162	T Morio. Recent advances in the study of immunodeficiency and DNA damage response. Int J Hematol. 2017;106(3):357-365.
163	CT Yan, C Boboila, EK Souza, et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007;449(7161):478-482.
164	C Boboila, C Yan, DR Wesemann, et al. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med. 2010;207(2):417-427.
165	A Kim Wiese, M Schluterman Burdine, RH Turnage, AJ Tackett, LJ Burdine. DNA-PKcs controls calcineurin mediated IL-2 production in T lymphocytes. PLoS One. 2017;12(7):e0181608.
166	MA Ghonim, K Pyakurel, J Ju, et al. DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4(+) T-cell function without causing severe combined immunodeficiency. J Allergy Clin Immunol. 2015;135(2):425-440.
167	J Kalous, D Aleshkina. Multiple roles of PLK1 in mitosis and meiosis. Cells. 2023;12(1):187.
168	B Huang, ZF Shang, B Li, et al. DNA-PKcs associates with PLK1 and is involved in proper chromosome segregation and cytokinesis. J Cell Biochem. 2014;115(6):1077-1088.
169	ZF Shang, B Huang, QZ Xu, et al. Inactivation of DNA-dependent protein kinase leads to spindle disruption and mitotic catastrophe with attenuated checkpoint protein 2 Phosphorylation in response to DNA damage. Cancer Res. 2010;70(9):3657-3666.
170	Q Hu, Y Xie, Y Ge, X Nie, J Tao, Y Zhao. Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway. Cell Death Dis. 2018;9(6):662.
171	DK Harrison, ZJ Waldrip, L Burdine, SC Shalin, MS Burdine. DNA-PKcs inhibition extends allogeneic skin graft survival. Transplantation. 2021;105(3):540-549.
172	J Ju, AS Naura, Y Errami, et al. Phosphorylation of p50 NF-kappaB at a single serine residue by DNA-dependent protein kinase is critical for VCAM-1 expression upon TNF treatment. J Biol Chem. 2010;285(52):41152-41160.
173	R Zou, J Tao, J Qiu, et al. DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction. J Adv Res. 2022;41:39-48.
174	L Shao, JJ Goronzy, CM Weyand. DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis. EMBO Mol Med. 2010;2(10):415-427.
175	K Zumer, AK Low, H Jiang, K Saksela, BM Peterlin. Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes. Mol Cell Biol. 2012;32(8):1354-1362.
176	S Espejel, M Martin, P Klatt, J Martin-Caballero, JM Flores, MA Blasco. Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice. EMBO Rep. 2004;5(5):503-509.
177	I Taniuchi. CD4 helper and CD8 cytotoxic T cell differentiation. Annu Rev Immunol. 2018;36:579-601.
178	J Sui, S Zhang, BPC Chen. DNA-dependent protein kinase in telomere maintenance and protection. Cell Mol Biol Lett. 2020;25:2.
179	SM Bailey, MN Cornforth, A Kurimasa, DJ Chen, EH Goodwin. Strand-specific postreplicative processing of mammalian telomeres. Science. 2001;293(5539):2462-2465.
180	H Lu, J Saha, PJ Beckmann, EA Hendrickson, AJ Davis. DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response. Nucleic Acids Res. 2019;47(18):9467-9479.
181	J Kanungo. DNA-dependent protein kinase and DNA repair: relevance to Alzheimer's disease. Alzheimers Res Ther. 2013;5(2):13.
182	DA Shackelford. DNA end joining activity is reduced in Alzheimer's disease. Neurobiol Aging. 2006;27(4):596-605.
183	V Davydov, LA Hansen, DA Shackelford. Is DNA repair compromised in Alzheimer's disease? Neurobiol Aging. 2003;24(7):953-968.
184	M Maor-Nof, Z Shipony, R Lopez-Gonzalez, et al. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell. 2021;184(3):689-708.e20.
185	R Lopez-Gonzalez, D Yang, M Pribadi, et al. Partial inhibition of the overactivated Ku80-dependent DNA repair pathway rescues neurodegeneration in C9ORF72-ALS/FTD. Proc Natl Acad Sci USA. 2019;116(19):9628-9633.
186	C Zhang, J Liu, D Xu, T Zhang, W Hu, Z Feng. Gain-of-function mutant p53 in cancer progression and therapy. J Mol Cell Biol. 2020;12(9):674-687.
187	J Liu, JR Naegele, SL Lin. The DNA-PK catalytic subunit regulates Bax-mediated excitotoxic cell death by Ku70 phosphorylation. Brain Res. 2009;1296:164-175.
188	R Hill, PW Lee. The DNA-dependent protein kinase (DNA-PK): more than just a case of making ends meet? Cell Cycle. 2010;9(17):3460-3469.
189	CJ Garwood, JE Simpson, S Al Mashhadi, et al. DNA damage response and senescence in endothelial cells of human cerebral cortex and relation to Alzheimer's neuropathology progression: a population-based study in the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort. Neuropathol Appl Neurobiol. 2014;40(7):802-814.
190	A Kannan, K Bhatia, D Branzei, L Gangwani. Combined deficiency of Senataxin and DNA-PKcs causes DNA damage accumulation and neurodegeneration in spinal muscular atrophy. Nucleic Acids Res. 2018;46(16):8326-8346.
191	M Medova, M Medo, L Hovhannisyan, C Munoz-Maldonado, DM Aebersold, Y Zimmer. DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions. Pharmacol Ther. 2020;215:107617.
192	M Toulany, KJ Lee, KR Fattah, et al. Akt promotes post-irradiation survival of human tumor cells through initiation, progression, and termination of DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Res. 2012;10(7):945-957.
193	JF Goodwin, V Kothari, JM Drake, et al. DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell. 2015;28(1):97-113.
194	I Teneng, MA Picchi, S Leng, et al. DNA-PKc deficiency drives pre-malignant transformation by reducing DNA repair capacity in concert with reprogramming the epigenome in human bronchial epithelial cells. DNA Repair (Amst). 2019;79:1-9.
195	H Yang, F Yao, TM Marti, RA Schmid, RW Peng. Beyond DNA repair: DNA-PKcs in tumor metastasis, metabolism and immunity. Cancers (Basel). 2020;12(11):3389.
196	T Li, J Fu, Z Zeng, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509-W514.
197	S-R Ho, Y-C Lee, MM Ittmann, F-T Lin, KS Chan, W-C Lin. RNF144A deficiency promotes PD-L1 protein stabilization and carcinogen-induced bladder tumorigenesis. Cancer Lett. 2021;520:344-360.
198	J Zhang, H Jiang, D Xu, WJ Wu, HD Chen, L He. DNA-PKcs mediates an epithelial-mesenchymal transition process promoting cutaneous squamous cell carcinoma invasion and metastasis by targeting the TGF-beta1/Smad signaling pathway. Onco Targets Ther. 2019;12:9395-9405.
199	JF Goodwin, KE Knudsen. Beyond DNA repair: DNA-PK function in cancer. Cancer Discov. 2014;4(10):1126-1139.
200	T Hisatomi, N Sueoka-Aragane, A Sato, et al. NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIalpha and DNA-dependent protein kinase. Blood. 2011;117(13):3575-3584.
201	I Rybanska, O Ishaq, J Chou, et al. PARP1 and DNA-PKcs synergize to suppress p53 mutation and telomere fusions during T-lineage lymphomagenesis. Oncogene. 2013;32(14):1761-1771.
202	J Ding, X Li, S Khan, et al. EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma. Neuro Oncol. 2022;24(10):1712-1725.
203	B Adamson, N Brittain, L Walker, et al. The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer. J Clin Invest. 2023;133(22).
204	Z Song, Y Xie, Z Guo, et al. Genome-wide identification of DNA-PKcs-associated RNAs by RIP-Seq. Signal Transduct Target Ther. 2019;4:22.
205	E Dylgjeri, V Kothari, AA Shafi, et al. A novel role for DNA-PK in metabolism by regulating glycolysis in castration-resistant prostate cancer. Clin Cancer Res. 2022;28(7):1446-1459.
206	P Dharanipragada, X Zhang, S Liu, et al. Blocking genomic instability prevents acquired resistance to MAPK inhibitor therapy in melanoma. Cancer Discov. 2023;13(4):880-909.
207	D Dibitetto, S Marshall, A Sanchi, et al. DNA-PKcs promotes fork reversal and chemoresistance. Mol Cell. 2022;82(20):3932-3942.e6.
208	FJ Groelly, M Porru, J Zimmer, et al. Anti-tumoural activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours. EMBO Mol Med. 2022;14(3):e14501.
209	J Zhang, M Chen, Y Pang, et al. Flap endonuclease 1 and DNA-PKcs synergistically participate in stabilizing replication fork to encounter replication stress in glioma cells. J Exp Clin Cancer Res. 2022;41(1):140.
210	Y Qu, J Feng, X Wu, et al. A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population. Nat Commun. 2022;13(1):2052.
211	W Yu, H Xu, Z Sun, et al. TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage. Acta Pharm Sin B. 2023;13(12):4823-4839.
212	L Wang, L Wu, Y Du, et al. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation. Redox Biol. 2023;67:102893.
213	HH Sutcu, B Montagne, M Ricchetti. DNA-PKcs regulates myogenesis in an Akt-dependent manner independent of induced DNA damage. Cell Death Differ. 2023;30(8):1900-1915.
214	Y Yang, S Liu, P Wang, et al. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice. Nat Commun. 2023;14(1):1334.
215	AW Goldrath, PV Sivakumar, M Glaccum, et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med. 2002;195(12):1515-1522.
216	Y Matsumoto. Development and evolution of DNA-dependent protein kinase inhibitors toward cancer therapy. Int J Mol Sci. 2022;23(8).
217	CR Timme, BH Rath, JW O'Neill, K Camphausen, PJ Tofilon. The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. Mol Cancer Ther. 2018;17(6):1207-1216.
218	X Fang, Z Huang, K Zhai, et al. Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Sci Transl Med. 2021;13(600).
219	RM Pascale, C Joseph, G Latte, M Evert, F Feo, DF Calvisi. DNA-PKcs: a promising therapeutic target in human hepatocellular carcinoma? DNA Repair (Amst). 2016;47:12-20.
220	A Mari?o-Enríquez, JP Novotny, DC Gulhan, et al. Hyper-dependence on NHEJ enables synergy between DNA-PK inhibitors and low-dose doxorubicin in leiomyosarcoma. Clin Cancer Res. 2023.
221	HC Wise, GV Iyer, K Moore, et al. Activity of M3814, an oral DNA-PK inhibitor, in combination with topoisomerase II inhibitors in ovarian cancer models. Sci Rep. 2019;9(1):18882.
222	M Wang, S Chen, Y Wei, X Wei. DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer. Acta Pharm Sin B. 2021;11(12):3935-3949.
223	AK Tsai, AY Khan, CE Worgo, LL Wang, Y Liang, E Davila. A multikinase and DNA-PK inhibitor combination immunomodulates melanomas, suppresses tumor progression, and enhances immunotherapies. Cancer Immunol Res. 2017;5(9):790-803.
224	JHL Fok, A Ramos-Montoya, M Vazquez-Chantada, et al. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat Commun. 2019;10(1):5065.
225	TGA Reuvers, NS Verkaik, D Stuurman, et al. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics. 2023;13(10):3117-3130.
226	C Le Tourneau, B Dreno, Y Kirova, et al. First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. Br J Cancer. 2016;114(11):1199-1205.
227	J Biau, F Devun, W Jdey, et al. A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma. Neoplasia. 2014;16(10):835-844.
228	DW Rasco, KP Papadopoulos, M Pourdehnad, et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin Cancer Res. 2019;25(1):90-98.
229	C Carpio, R Bouabdallah, L Ysebaert, et al. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood. 2020;135(13):996-1007.
230	DJ George, S Halabi, P Healy, et al. Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer. Prostate. 2019;79(15):1752-1761.
231	E Dylgjeri, C McNair, JF Goodwin, et al. Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies. Clin Cancer Res. 2019;25(18):5623-5637.
232	D Huang, WL Kraus. The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Mol Cell. 2022;82(12):2315-2334.
233	WY Mansour, T Rhein, J Dahm-Daphi. The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Res. 2010;38(18):6065-6077.
234	S Ying, Z Chen, AL Medhurst, et al. DNA-PKcs and PARP1 bind to unresected stalled DNA replication forks where they recruit XRCC1 to mediate repair. Cancer Res. 2016;76(5):1078-1088.
235	JC Brenner, B Ateeq, Y Li, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19(5):664-678.
236	M Sajish, Q Zhou, S Kishi, et al. Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling. Nat Chem Biol. 2012;8(6):547-554.
237	C Wang, H Tang, A Geng, et al. Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors. Proc Natl Acad Sci USA. 2020;117(42):26356-26365.
238	O Shoshani, SF Brunner, R Yaeger, et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature. 2021;591(7848):137-141.
239	T Ortiz, MA Burguillos, G Lopez-Lluch, et al. Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin. Radiat Environ Biophys. 2008;47(4):445-452.
240	L Yang, Y Liu, C Sun, et al. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation. Oncol Lett. 2015;10(5):2856-2864.
241	RL Gurung, HK Lim, S Venkatesan, PS Lee, MP Hande. Targeting DNA-PKcs and telomerase in brain tumour cells. Mol Cancer. 2014;13:232.
242	JJ Jacobs, K Kieboom, S Marino, RA DePinho, M van Lohuizen. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999;397(6715):164-168.
243	CD Scharer, BG Barwick, BA Youngblood, R Ahmed, JM Boss. Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol (Baltimore, Md: 1950). 2013;191(6):3419-3429.
244	SL Elliott, C Crawford, E Mulligan, et al. Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia. Br J Haematol. 2011;152(1):61-71.
245	CE Willoughby, Y Jiang, HD Thomas, et al. Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy. J Clin Invest. 2020;130(1):258-271.
246	TM Gottlieb, SP Jackson. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 1993;72(1):131-142.
247	S Imseng, CH Aylett, T Maier. Architecture and activation of phosphatidylinositol 3-kinase related kinases. Curr Opin Struct Biol. 2018;49:177-189.
248	Q Ding, YV Reddy, W Wang, et al. Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair. Mol Cell Biol. 2003;23(16):5836-5848.
249	P Douglas, X Cui, WD Block, et al. The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol. 2007;27(5):1581-1591.
250	HS Lee, G Choe, KU Park, et al. Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer. Int J Oncol. 2007;31(4):859-866.
251	SS He, Y Chen, XM Shen, et al. DNA-dependent protein kinase catalytic subunit functions in metastasis and influences survival in advanced-stage laryngeal squamous cell carcinoma. J Cancer. 2017;8(12):2410-2416.
252	J Xing, X Wu, AA Vaporciyan, MR Spitz, J Gu. Prognostic significance of ataxia-telangiectasia mutated, DNA-dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86-kD subunit expression in patients with nonsmall cell lung cancer. Cancer. 2008;112(12):2756-2764.
253	F Ren, ZL Yang, X Tan, et al. DNA-PKcs and Ku70 are predictive markers for poor prognosis of patients with gall bladder malignancies. Appl Immunohistochem Mol Morphol. 2014;22(10):741-747.
254	M Evert, M Frau, ML Tomasi, et al. Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value. Br J Cancer. 2013;109(10):2654-2664.
255	S Selvaraj, WN Feist, S Viel, et al. High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition. Nat Biotechnol. 2024;42(5):731-744.
256	B van de Kooij, A Kruswick, H van Attikum, MB Yaffe. Multi-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks. Nat Commun. 2022;13(1):5295.