[Frontiers in Bioscience, Landmark, 25, 1538-1567, March 1, 2020]

Structural and strategic landscape of PIKK protein family and their inhibitors: an overview

Deekshi Angira1, Althaf Shaik1, Vijay Thiruvenkatam2

1Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India-382355, 2Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India-382355

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Diverse kinases in PIKK protein family
    3.1. Mammalian target of Rapamycin (mTOR)
      3.1.1. Architectural framework of mTOR as the basis for inhibitor design
      3.1.2. mTOR inhibitors
         3.1.2.1. Rapamycin and rapalogs- allosteric inhibitors
         3.1.2.2. ATP competitive and irreversible inhibitor for mTOR
    3.2. Ataxia-telangiectasia mutated (ATM)
      3.2.1. Domain organization and active-site facet of ATM
      3.2.2. Quinolines as ATM inhibitors
    3.3. Ataxia-telangiectasia mutated- and Rad3-related (ATR)
      3.3.1. ATR-A key sensor to DNA damage repair and stalled replication forks
      3.3.2. Pyrazine amine derivatives as selective ATR inhibitors
    3.4. DNA dependent protein kinase catalytic subunit (DNA-PKcs)
      3.4.1. Structural dynamics of DNA-PKcs
      3.4.2. Inhibitors against DNA-PKcs
    3.5. Transformation/transcription domain-associated protein (TRRAP)
      3.5.1. TRRAP: An exceptional PIKK family member deficient in kinase activity
    3.6. Human Suppressor with morphological effect on genitalia family member (hSMG1)
      3.6.1. hSMG1: The mRNA surveillance protein
      3.6.2. Pyramidine amine deriviatives as selective hSMG inhibitors
4. Conclusion
5. Future perspectives
6. Acknowledgments
7. References

1. ABSTRACT

Phosphatidylinositol-3 kinase-related kinases (PIKKs) is a class of six unique serine/threonine kinases that are characterized as high molecular mass colossal proteins present in multicellular organisms. They predominantly regulate the innumerable eukaryotic cellular processes, for instance, cell-signaling cascades related to DNA damage and repair, cell growth and proliferation, cell cycle arrest, genome surveillance, gene expression and many other important yet diverse functions. A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain. In this comprehensive review, we reassess and discuss various established functions of all the six PIKK members with each function corroborated by their structural topology. In addition to the domain architecture of these atypical kinases, their specific inhibitors have been briefly deliberated. This review gives us the impression of the emergent importance of PIKKs, which, despite of their complexity, are the hub of research with respect to the inhibitor development.

7. REFERENCES

1. SP Jackson, J Bartek: The DNA-damage response in human biology and disease. Nature 461, 1071-1078 (2009)
DOI: 10.1038/nature08467
PMid:19847258 PMCid:PMC2906700

2. MR V Finlay, RJ Griffin. Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family. Bioorg Med Chem Lett 22, 5352-5359 (2012)
DOI: 10.1016/j.bmcl.2012.06.053
PMid:22835870

3. CT Keith, SL Schreiber. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270, 50-51 (1995)
DOI: 10.1126/science.270.5233.50
PMid:7569949

4. T Hunter. When is a lipid kinase not a lipid kinase? When it is a protein kinase. Cell 83, 1-4 (1995)
DOI: 10.1016/0092-8674(95)90225-2

5. G Manning, DB Whyte, R Martinez, T Hunter, S Sudarsanam. The Protein Kinase Complement of the Human Genome. Science (80 ) 298, 1912 LP-1934 (2002)
DOI: 10.1126/science.1075762
PMid:12471243

6. RT Abraham. PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst) 3, 883-887 (2004)
DOI: 10.1016/j.dnarep.2004.04.002
PMid:15279773

7. H Lempiäinen, TD Halazonetis. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J 28, 3067-3073 (2009)
DOI: 10.1038/emboj.2009.281
PMid:19779456 PMCid:PMC2752028

8. GCM Smith, SP Jackson. Chapter 77 - The PIKK Family of Protein Kinases. In: RA Bradshaw, EABT-H of CS (Second E Dennis, eds. , Academic Press, San Diego (2010)
DOI: 10.1016/B978-0-12-374145-5.00077-2
PMCid:PMC3091723

9. CA Lovejoy, D Cortez. Common mechanisms of PIKK regulation. DNA Repair (Amst) 8, 1004-1008 (2009)
DOI: 10.1016/j.dnarep.2009.04.006
PMid:19464237 PMCid:PMC2725225

10. S Imseng, CHS Aylett, T Maier. Architecture and activation of phosphatidylinositol 3-kinase related kinases. Curr Opin Struct Biol 49, 177-189 (2018)
DOI: 10.1016/j.sbi.2018.03.010
PMid:29625383

11. DA Mordes, D Cortez. Activation of ATR and related PIKKs. Cell Cycle 7, 2809-2812 (2008)
DOI: 10.4161/cc.7.18.6689
PMid:18769153 PMCid:PMC2672405

12. J Falck, J Coates, SP Jackson. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605-611 (2005)
DOI: 10.1038/nature03442
PMid:15758953

13. KA Cimprich, D Cortez. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9, 616-627 (2008)
DOI: 10.1038/nrm2450
PMid:18594563 PMCid:PMC2663384

14. MF Lavin. ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 26, 7749-7758 (2007)
DOI: 10.1038/sj.onc.1210880
PMid:18066087

15. GC Smith, SP Jackson. The DNA-dependent protein kinase. Genes Dev 13, 916-934 (1999)
DOI: 10.1101/gad.13.8.916
PMid:10215620

16. Y Sancak, TR Peterson, YD Shaul, RA Lindquist, CC Thoreen, L Bar-Peled, DM Sabatini. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501 (2008)
DOI: 10.1126/science.1157535
PMid:18497260 PMCid:PMC2475333

17. I Kashima, A Yamashita, N Izumi, N Kataoka, R Morishita, S Hoshino, M Ohno, G Dreyfuss, S Ohno. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev 20, 355-367 (2006)
DOI: 10.1101/gad.1389006
PMid:16452507 PMCid:PMC1361706

18. SB McMahon, HA Van Buskirk, KA Dugan, TD Copeland, MD Cole. The Novel ATM-Related Protein TRRAP Is an Essential Cofactor for the c-Myc and E2F Oncoproteins. Cell 94, 363-374 (1998)
DOI: 10.1016/S0092-8674(00)81479-8

19. J Heitman, NR Movva, MN Hall. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-909 (1991)
DOI: 10.1126/science.1715094
PMid:1715094

20. GP Livi. Halcyon days of TOR: Reflections on the multiple independent discovery of the yeast and mammalian TOR proteins. Gene 692, 145-155 (2019)
DOI: 10.1016/j.gene.2018.12.046
PMid:30639424

21. Y Xiong, J Sheen. The role of target of rapamycin signaling networks in plant growth and metabolism. Plant Physiol 164, 499-512 (2014)
DOI: 10.1104/pp.113.229948
PMid:24385567 PMCid:PMC3912084

22. R Loewith, E Jacinto, S Wullschleger, A Lorberg, JL Crespo, D Bonenfant, W Oppliger, P Jenoe, MN Hall. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10, 457-468 (2002)
DOI: 10.1016/S1097-2765(02)00636-6

23. H Yang, DG Rudge, JD Koos, B Vaidialingam, HJ Yang, NP Pavletich. mTOR kinase structure, mechanism and regulation. Nature 497, 217-223 (2013)
DOI: 10.1038/nature12122
PMid:23636326 PMCid:PMC4512754

24. K Singh, S Sun, C Vezina. Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action. J Antibiot (Tokyo) 32, 630-645 (1979)
DOI: 10.7164/antibiotics.32.630
PMid:381274

25. SN Sehgal, H Baker, C Vezina. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 28, 727-732 (1975)
DOI: 10.7164/antibiotics.28.727
PMid:1102509

26. L Meng, XFS Zheng. Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin 36, 1163-1169 (2015)
DOI: 10.1038/aps.2015.68
PMid:26299952 PMCid:PMC4648176

27. F Riccardi, G Colantuoni, A Diana, C Mocerino, G Carteni, R Lauria, A Febbraro, F Nuzzo, R Addeo, O Marano, P Incoronato, S De Placido, F Ciardiello, M Orditura. Exemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety. Mol Clin Oncol 9, 255-263 (2018)
DOI: 10.3892/mco.2018.1672
PMid:30155246 PMCid:PMC6109668

28. J Baselga, M Campone, M Piccart, HA Burris, HS Rugo, T Sahmoud, S Noguchi, M Gnant, KI Pritchard, F Lebrun, JT Beck, Y Ito, D Yardley, I Deleu, A Perez, T Bachelot, L Vittori, Z Xu, P Mukhopadhyay, D Lebwohl, GN Hortobagyi. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 366, 520-529 (2011)
DOI: 10.1056/NEJMoa1109653
PMid:22149876 PMCid:PMC5705195

29. PJ de Vries, DN Franz, P Curatolo, R Nabbout, M Neary, F Herbst, K Sully, E Brohan, B Bennett, JA Lawson. Measuring Health-Related Quality of Life in Tuberous Sclerosis Complex - Psychometric Evaluation of Three Instruments in Individuals With Refractory Epilepsy. Front Pharmacol 9, 964 (2018)
DOI: 10.3389/fphar.2018.00964
PMid:30214408 PMCid:PMC6126421

30. P Curatolo, DN Franz, JA Lawson, Z Yapici, H Ikeda, T Polster, R Nabbout, PJ de Vries, DJ Dlugos, J Fan, A Ridolfi, D Pelov, M Voi, JA French. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Heal 2, 495-504 (2018)
DOI: 10.1016/S2352-4642(18)30099-3

31. JA French, JA Lawson, Z Yapici, H Ikeda, T Polster, R Nabbout, P Curatolo, PJ de Vries, DJ Dlugos, N Berkowitz, M Voi, S Peyrard, D Pelov, DN Franz. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet (London, England) 388, 2153-2163 (2016)
DOI: 10.1016/S0140-6736(16)31419-2

32. I Goyer, N Dahdah, P Major. Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol 52, 450-453 (2015)
DOI: 10.1016/j.pediatrneurol.2015.01.004
PMid:25682485

33. S Schenone, C Brullo, F Musumeci, M Radi, M Botta. ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 18, 2995-3014 (2011)
DOI: 10.2174/092986711796391651
PMid:21651476

34. Q Liu, C Xu, S Kirubakaran, X Zhang, W Hur, Y Liu, NP Kwiatkowski, J Wang, KD Westover, P Gao, D Ercan, M Niepel, CC Thoreen, SA Kang, MP Patricelli, Y Wang, T Tupper, A Altabef, H Kawamura, KD Held, DM Chou, SJ Elledge, PA Janne, K-K Wong, DM Sabatini, NS Gray. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res 73, 2574-2586 (2013)
DOI: 10.1158/0008-5472.CAN-12-1702
PMid:23436801 PMCid:PMC3760004

35. Q Liu, J Wang, SA Kang, CC Thoreen, W Hur, T Ahmed, DM Sabatini, NS Gray. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2( 1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem 54, 1473-1480 (2011)
DOI: 10.1021/jm101520v
PMid:21322566 PMCid:PMC3090687

36. A Shaik, R Bhakuni, S Kirubakaran. Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors. Molecules 23 (2018)
DOI: 10.3390/molecules23050992
PMid:29695073 PMCid:PMC6102578

37. C Li, J-F Cui, M-B Chen, C-Y Liu, F Liu, Q-D Zhang, J Zou, P-H Lu. The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. Cancer Biol Ther 16, 34-42 (2015)
DOI: 10.4161/15384047.2014.972274
PMid:25692620 PMCid:PMC4623257

38. H Miyahara, S Yadavilli, M Natsumeda, JA Rubens, L Rodgers, M Kambhampati, IC Taylor, H Kaur, L Asnaghi, CG Eberhart, KE Warren, J Nazarian, EH Raabe. The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma. Cancer Lett 400, 110-116 (2017)
DOI: 10.1016/j.canlet.2017.04.019
PMid:28450157 PMCid:PMC5569904

39. S V Bhagwat, PC Gokhale, AP Crew, A Cooke, Y Yao, C Mantis, J Kahler, J Workman, M Bittner, L Dudkin, DM Epstein, NW Gibson, R Wild, LD Arnold, PJ Houghton, JA Pachter. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Mol Cancer Ther 10, 1394-1406 (2011)
DOI: 10.1158/1535-7163.MCT-10-1099
PMid:21673091

40. CM Chresta, BR Davies, I Hickson, T Harding, S Cosulich, SE Critchlow, JP Vincent, R Ellston, D Jones, P Sini, D James, Z Howard, P Dudley, G Hughes, L Smith, S Maguire, M Hummersone, K Malagu, K Menear, R Jenkins, M Jacobsen, GCM Smith, S Guichard, M Pass. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 70, 288-298 (2010)
DOI: 10.1158/0008-5472.CAN-09-1751
PMid:20028854

41. M Bonora, MR Wieckowsk, C Chinopoulos, O Kepp, G Kroemer, L Galluzzi, P Pinton. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34, 1475-86 (2015)
DOI: 10.1038/onc.2014.96
DOI: 10.1038/onc.2014.462

42. BH Norman, C Shih, JE Toth, JE Ray, JA Dodge, DW Johnson, PG Rutherford, RM Schultz, JF Worzalla, CJ Vlahos. Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. J Med Chem 39, 1106-1111 (1996)
DOI: 10.1021/jm950619p
PMid:8676346

43. NT Ihle, R Williams, S Chow, W Chew, MI Berggren, G Paine-Murrieta, DJ Minion, RJ Halter, P Wipf, R Abraham, L Kirkpatrick, G Powis. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3, 763-772 (2004)

44. MSY Huen, J Chen. The DNA damage response pathways: at the crossroad of protein modifications. Cell Res 18, 8 (2007)
DOI: 10.1038/cr.2007.109
PMid:18087291

45. D Delia, S Mizutani. The DNA damage response pathway in normal hematopoiesis and malignancies. Int J Hematol 106, 328-334 (2017)
DOI: 10.1007/s12185-017-2300-7
PMid:28707218

46. D Cortez, Y Wang, J Qin, SJ Elledge. Requirement of ATM-Dependent Phosphorylation of Brca1 in the DNA Damage Response to Double-Strand Breaks. Science (80- ) 286, 1162 LP-1166 (1999)
DOI: 10.1126/science.286.5442.1162
PMid:10550055

47. J-H Lee, TT Paull. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551-554 (2005)
DOI: 10.1126/science.1108297
PMid:15790808

48. 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 22, 5612-5621 (2003)
DOI: 10.1093/emboj/cdg541
PMid:14532133 PMCid:PMC213795

49. K Savitsky, A Bar-Shira, S Gilad, G Rotman, Y Ziv, L Vanagaite, DA Tagle, S Smith, T Uziel, S Sfez, M Ashkenazi, I Pecker, M Frydman, R Harnik, SR Patanjali, A Simmons, GA Clines, A Sartiel, RA Gatti, L Chessa, O Sanal, MF Lavin, NG Jaspers, AM Taylor, CF Arlett, T Miki, SM Weissman, M Lovett, FS Collins, Y Shiloh. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749-1753 (1995)
DOI: 10.1126/science.7792600
PMid:7792600

50. PW Greenwell, SL Kronmal, SE Porter, J Gassenhuber, B Obermaier, TD Petes. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 82, 823-829 (1995)
DOI: 10.1016/0092-8674(95)90479-4

51. S Burma, BP Chen, M Murphy, A Kurimasa, DJ Chen. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276, 42462-42467 (2001)
DOI: 10.1074/jbc.C100466200
PMid:11571274

52. M Shen, Z Xu, W Xu, K Jiang, F Zhang, Q Ding, Z Xu, Y Chen. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer Res 38, 149 (2019)
DOI: 10.1186/s13046-019-1161-8
PMid:30961670 PMCid:PMC6454747

53. X Wang, H Chu, M Lv, Z Zhang, S Qiu, H Liu, X Shen, W Wang, G Cai. Structure of the intact ATM/Tel1 kinase. Nat Commun 7, 11655 (2016)
DOI: 10.1038/ncomms11655
PMid:27229179 PMCid:PMC4894967

54. D Baretić, HK Pollard, DI Fisher, CM Johnson, B Santhanam, CM Truman, T Kouba, AR Fersht, C Phillips, RL Williams. Structures of closed and open conformations of dimeric human ATM. Sci Adv 3, e1700933 (2017)
DOI: 10.1126/sciadv.1700933
PMid:28508083 PMCid:PMC5425235

55. B Mukherjee, N Tomimatsu, K Amancherla, C V Camacho, N Pichamoorthy, S Burma. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 14, 34-43 (2012)
DOI: 10.1593/neo.111512
PMid:22355272 PMCid:PMC3281940

56. M Toyoda, K Watanabe, T Amagasaki, K Natsume, H Takeuchi, C Quadt, K Shirao, H Minami. A phase I study of single-agent BEZ235 special delivery system sachet in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 83, 289-299 (2019)
DOI: 10.1007/s00280-018-3725-2
PMid:30446785 PMCid:PMC6394493

57. SL Degorce, B Barlaam, E Cadogan, A Dishington, R Ducray, SC Glossop, LA Hassall, F Lach, A Lau, TM McGuire, T Nowak, G Ouvry, KG Pike, AG Thomason. Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase. J Med Chem 59, 6281-6292 (2016)
DOI: 10.1021/acs.jmedchem.6b00519
PMid:27259031

58. B Barlaam, E Cadogan, A Campbell, N Colclough, A Dishington, S Durant, K Goldberg, LA Hassall, GD Hughes, PA MacFaul, TM McGuire, M Pass, A Patel, S Pearson, J Petersen, KG Pike, G Robb, N Stratton, G Xin, B Zhai. Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors. ACS Med Chem Lett 9, 809-814 (2018)
DOI: 10.1021/acsmedchemlett.8b00200
PMid:30128072 PMCid:PMC6088353

59. HY Yoo, A Shevchenko, A Shevchenko, WG Dunphy. Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J Biol Chem 279, 53353-53364 (2004)
DOI: 10.1074/jbc.M408026200
PMid:15448142

60. JM Wagner, SH Kaufmann. Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals (Basel) 3, 1311-1334 (2010)
DOI: 10.3390/ph3051311
PMid:27713304 PMCid:PMC4033983

61. L Zou, SJ Elledge. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542-1548 (2003)
DOI: 10.1126/science.1083430
PMid:12791985

62. V Ellison, B Stillman. Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNA. PLoS Biol 1, E33 (2003)
DOI: 10.1371/journal.pbio.0000033
PMid:14624239 PMCid:PMC261875

63. A Kumagai, J Lee, HY Yoo, WG Dunphy. TopBP1 activates the ATR-ATRIP complex. Cell 124, 943-955 (2006)
DOI: 10.1016/j.cell.2005.12.041
PMid:16530042

64. J Yang, Z-P Xu, Y Huang, HE Hamrick, PJ Duerksen-Hughes, Y-N Yu. ATM and ATR: sensing DNA damage. World J Gastroenterol 10, 155-160 (2004)
DOI: 10.3748/wjg.v10.i2.155
PMid:14716813 PMCid:PMC4716994

65. J-S Liu, S-R Kuo, T Melendy. Phosphorylation of replication protein A by S-phase checkpoint kinases. DNA Repair (Amst) 5, 369-380 (2006)
DOI: 10.1016/j.dnarep.2005.11.007
PMid:16412704

66. J Chen. Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res 60, 5037-5039 (2000)

67. Q Rao, M Liu, Y Tian, Z Wu, Y Hao, L Song, Z Qin, C Ding, H-W Wang, J Wang, Y Xu. Cryo-EM structure of human ATR-ATRIP complex. Cell Res 28, 143-156 (2018)
DOI: 10.1038/cr.2017.158
PMid:29271416 PMCid:PMC5799817

68. GH O'Sullivan Coyne, S Kummar, RS Meehan, L Juwara, R Piekarz, E Sharon, H Streicher, BA Conley, N Takebe, L Harris, A Doyle, MF Quinn, L Rubinstein, D Wilsker, RJ Kinders, RE Parchment, EB Levy, JH Doroshow, AP Chen. Phase I trial of the triplet veliparib + VX-970 + cisplatin in patients with advanced solid tumors. J Clin Oncol 35, TPS2609-TPS2609 (2017)
DOI: 10.1200/JCO.2017.35.15_suppl.TPS2609

69. ER Plummer, EJ Dean, TRJ Evans, A Greystoke, K Herbschleb, M Ranson, J Brown, Y Zhang, S Karan, J Pollard, MS Penney, M Asmal, SZ Fields, MR Middleton. Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792). J Clin Oncol 34, 2513 (2016)
DOI: 10.1200/JCO.2016.34.15_suppl.2513

70. R Josse, SE Martin, R Guha, P Ormanoglu, TD Pfister, PM Reaper, CS Barnes, J Jones, P Charlton, JR Pollard, J Morris, JH Doroshow, Y Pommier. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res 74, 6968-6979 (2014)
DOI: 10.1158/0008-5472.CAN-13-3369
PMid:25269479 PMCid:PMC4252598

71. N Jette, SP Lees-Miller. The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis. Prog Biophys Mol Biol 117, 194-205 (2015)
DOI: 10.1016/j.pbiomolbio.2014.12.003
PMid:25550082 PMCid:PMC4502593

72. JF Goodwin, KE Knudsen. Beyond DNA Repair: DNA-PK Function in Cancer. Cancer Discov 4, 1126 LP-1139 (2014)
DOI: 10.1158/2159-8290.CD-14-0358
PMid:25168287 PMCid:PMC4184981

73. S Britton, C Froment, P Frit, B Monsarrat, B Salles, P Calsou. Cell nonhomologous end joining capacity controls SAF-A phosphorylation by DNA-PK in response to DNA double-strand breaks inducers. Cell Cycle 8, 3717-3722 (2009)
DOI: 10.4161/cc.8.22.10025
PMid:19844162

74. FM Berglund, PR Clarke. hnRNP-U is a specific DNA-dependent protein kinase substrate phosphorylated in response to DNA double-strand breaks. Biochem Biophys Res Commun 381, 59-64 (2009)
DOI: 10.1016/j.bbrc.2009.02.019
PMid:19351595

75. P Douglas, R Ye, L Trinkle-Mulcahy, JA Neal, V De Wever, NA Morrice, K Meek, SP Lees-Miller. Polo-like kinase 1 (PLK1) and protein phosphatase 6 (PP6) regulate DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation in mitosis. Biosci Rep 34, e00113 (2014)
DOI: 10.1042/BSR20140051
PMid:24844881 PMCid:PMC4069685

76. A Cooper, M García, C Petrovas, T Yamamoto, RA Koup, GJ Nabel. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 498, 376 (2013)
DOI: 10.1038/nature12274
PMid:23739328

77. SP Lees-Miller, MC Long, MA Kilvert, V Lam, SA Rice, CA Spencer. Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0. J Virol 70, 7471 LP-7477 (1996)
DOI: 10.1128/JVI.70.11.7471-7477.1996
PMid:8892865 PMCid:PMC190814

78. BL Sibanda, DY Chirgadze, TL Blundell. Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature 463, 118-121 (2010)
DOI: 10.1038/nature08648
PMid:20023628 PMCid:PMC2811870

79. BL Sibanda, DY Chirgadze, DB Ascher, TL Blundell. DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair. Science (80- ) 355, 520 LP-524 (2017)
DOI: 10.1126/science.aak9654
PMid:28154079

80. H Sharif, Y Li, Y Dong, L Dong, WL Wang, Y Mao, H Wu. Cryo-EM structure of the DNA-PK holoenzyme. Proc Natl Acad Sci U S A 114, 7367-7372 (2017)
DOI: 10.1073/pnas.1707386114
PMid:28652322 PMCid:PMC5514765

81. IH Ismail, S Mårtensson, D Moshinsky, A Rice, C Tang, A Howlett, G McMahon, O Hammarsten. SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization. Oncogene 23, 873 (2003)
DOI: 10.1038/sj.onc.1207303
PMid:14661061

82. RA Izzard, SP Jackson, GCM Smith. Competitive and Noncompetitive Inhibition of the DNA-dependent Protein Kinase. Cancer Res 59, 2581 LP-2586 (1999)

83. P Peddi, CW Loftin, JS Dickey, JM Hair, KJ Burns, K Aziz, DC Francisco, MI Panayiotidis, OA Sedelnikova, WM Bonner, TA Winters, AG Georgakilas. DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells. Free Radic Biol Med 48, 1435-1443 (2010)
DOI: 10.1016/j.freeradbiomed.2010.02.033
PMid:20193758 PMCid:PMC2901171

84. BP Nutley, NF Smith, A Hayes, LR Kelland, L Brunton, BT Golding, GCM Smith, NMB Martin, P Workman, FI Raynaud. Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br J Cancer 93, 1011-1018 (2005)
DOI: 10.1038/sj.bjc.6602823
PMid:16249792 PMCid:PMC2361671

85. D Davidson, L Amrein, L Panasci, R Aloyz. Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond. Front Pharmacol 4, 5 (2013)
DOI: 10.3389/fphar.2013.00005
PMid:23386830 PMCid:PMC3560216

86. JJ Hollick, BT Golding, IR Hardcastle, N Martin, C Richardson, LJM Rigoreau, GCM Smith, RJ Griffin. 2,6-Disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK). Bioorg Med Chem Lett 13, 3083-3086 (2003)
DOI: 10.1016/S0960-894X(03)00652-8

87. S Ihmaid, HEA Ahmed, A Al-Sheikh Ali, YE Sherif, HM Tarazi, SM Riyadh, MF Zayed, HS Abulkhair, HS Rateb. Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors. Bioorg Chem 72, 234-247 (2017)
DOI: 10.1016/j.bioorg.2017.04.014
PMid:28482264

88. L Deleu, S Shellard, K Alevizopoulos, B Amati, H Land. Recruitment of TRRAP required for oncogenic transformation by E1A. Oncogene 20, 8270 (2001)
DOI: 10.1038/sj.onc.1205159
PMid:11781841

89. A Vassilev, J Yamauchi, T Kotani, C Prives, ML Avantaggiati, J Qin, Y Nakatani. The 400 kDa Subunit of the PCAF Histone Acetylase Complex Belongs to the ATM Superfamily. Mol Cell 2, 869-875 (1998)
DOI: 10.1016/S1097-2765(00)80301-9

90. F Robert, S Hardy, Z Nagy, C Baldeyron, R Murr, U Déry, J-Y Masson, D Papadopoulo, Z Herceg, L Tora. The transcriptional histone acetyltransferase cofactor TRRAP associates with the MRN repair complex and plays a role in DNA double-strand break repair. Mol Cell Biol 26, 402-412 (2006)
DOI: 10.1128/MCB.26.2.402-412.2006
PMid:16382133 PMCid:PMC1346889

91. R Murr, JI Loizou, Y-G Yang, C Cuenin, H Li, Z-Q Wang, Z Herceg. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol 8, 91 (2005)
DOI: 10.1038/ncb1343
PMid:16341205

92. M DeRan, M Pulvino, E Greene, C Su, J Zhao. Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition. Mol Cell Biol 28, 435-447 (2008)
DOI: 10.1128/MCB.00607-07
PMid:17967892 PMCid:PMC2223310

93. SB McMahon, MA Wood, MD Cole. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 20, 556-562 (2000)
DOI: 10.1128/MCB.20.2.556-562.2000
PMid:10611234 PMCid:PMC85131

94. M Brand, K Yamamoto, A Staub, L Tora. Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction. J Biol Chem 274, 18285-18289 (1999)
DOI: 10.1074/jbc.274.26.18285
PMid:10373431

95. T Ikura, V V Ogryzko, M Grigoriev, R Groisman, J Wang, M Horikoshi, R Scully, J Qin, Y Nakatani. Involvement of the TIP60 Histone Acetylase Complex in DNA Repair and Apoptosis. Cell 102, 463-473 (2000)
DOI: 10.1016/S0092-8674(00)00051-9

96. PG Ard, C Chatterjee, S Kunjibettu, LR Adside, LE Gralinski, SB McMahon. Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Mol Cell Biol 22, 5650-5661 (2002)
DOI: 10.1128/MCB.22.16.5650-5661.2002
PMid:12138177 PMCid:PMC133988

97. Z Herceg, W Hulla, D Gell, C Cuenin, M Lleonart, S Jackson, ZQ Wang. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet 29, 206-211 (2001)
DOI: 10.1038/ng725
PMid:11544477

98. LM Díaz-Santín, N Lukoyanova, E Aciyan, AC Cheung. Cryo-EM structure of the SAGA and NuA4 coactivator subunit Tra1 at 3.7 angstrom resolution. Elife 6, e28384 (2017)
DOI: 10.7554/eLife.28384
PMid:28767037 PMCid:PMC5576489

99. X Wang, S Ahmad, Z Zhang, J Côté, G Cai. Architecture of the Saccharomyces cerevisiae NuA4/TIP60 complex. Nat Commun 9, 1147 (2018)
DOI: 10.1038/s41467-018-03504-5
PMid:29559617 PMCid:PMC5861120

100. A Yamashita, T Ohnishi, I Kashima, Y Taya, S Ohno. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev 15, 2215-2228 (2001)
DOI: 10.1101/gad.913001
PMid:11544179 PMCid:PMC312771

101. R Melero, A Uchiyama, R Castaño, N Kataoka, H Kurosawa, S Ohno, A Yamashita, O Llorca. Structures of SMG1-UPFs Complexes: SMG1 Contributes to Regulate UPF2-Dependent Activation of UPF1 in NMD. Structure 22, 1105-1119 (2014)
DOI: 10.1016/j.str.2014.05.015
PMid:25002321

102. RT Abraham. The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways. DNA Repair (Amst) 3, 919-925 (2004)
DOI: 10.1016/j.dnarep.2004.04.003
PMid:15279777

103. P V Ivanov, NH Gehring, JB Kunz, MW Hentze, AE Kulozik. Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J 27, 736 LP-747 (2008)
DOI: 10.1038/emboj.2008.17
PMid:18256688 PMCid:PMC2265754

104. G Denning, L Jamieson, LE Maquat, EA Thompson, AP Fields. Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein. J Biol Chem 276, 22709-22714 (2001)
DOI: 10.1074/jbc.C100144200
PMid:11331269

105. KM Brumbaugh, DM Otterness, C Geisen, V Oliveira, J Brognard, X Li, F Lejeune, RS Tibbetts, LE Maquat, RT Abraham. The mRNA Surveillance Protein hSMG-1 Functions in Genotoxic Stress Response Pathways in Mammalian Cells. Mol Cell 14, 585-598 (2004)
DOI: 10.1016/j.molcel.2004.05.005
PMid:15175154

106. V Oliveira, WJ Romanow, C Geisen, DM Otterness, F Mercurio, HG Wang, WS Dalton, RT Abraham. A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosis. J Biol Chem 283, 13174-13184 (2008)
DOI: 10.1074/jbc.M708008200
PMid:18326048 PMCid:PMC2442360

107. E Arias-Palomo, A Yamashita, IS Fernandez, R Nunez-Ramirez, Y Bamba, N Izumi, S Ohno, O Llorca. The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes Dev 25, 153-164 (2011)
DOI: 10.1101/gad.606911
PMid:21245168 PMCid:PMC3022261

108. J Perry, N Kleckner. The ATRs, ATMs, and TORs Are Giant HEAT Repeat Proteins. Cell 112, 151-155 (2003)
DOI: 10.1016/S0092-8674(03)00033-3

109. A Deniaud, F Garzoni, K Huard, M Karuppasamy, S Masiulis, C Schaffitzel, M Beck, T Bock, AE Kulozik, G Neu-Yilik, K Kerschgens, MW Hentze. A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation. Nucleic Acids Res 43, 7600-7611 (2015)
DOI: 10.1093/nar/gkv668
PMid:26130714 PMCid:PMC4551919

110. A Gopalsamy, EM Bennett, M Shi, W-G Zhang, J Bard, K Yu. Identification of pyrimidine derivatives as hSMG-1 inhibitors. Bioorg Med Chem Lett 22, 6636-6641 (2012)
DOI: 10.1016/j.bmcl.2012.08.107
PMid:23021994

111. LI Toledo, M Murga, R Zur, R Soria, A Rodriguez, S Martinez, J Oyarzabal, J Pastor, JR Bischoff, O Fernandez-Capetillo. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18, 721-727 (2011)
DOI: 10.1038/nsmb.2076
PMid:21552262 PMCid:PMC4869831

112. M Hidalgo, JC Buckner, C Erlichman, MS Pollack, JP Boni, G Dukart, B Marshall, L Speicher, L Moore, EK Rowinsky. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12, 5755-5763 (2006)
DOI: 10.1158/1078-0432.CCR-06-0118
PMid:17020981

113. RJ Amato, J Jac, S Giessinger, S Saxena, JP Willis. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 115, 2438-2446 (2009)
DOI: 10.1002/cncr.24280
PMid:19306412

114. KG Pike, K Malagu, MG Hummersone, KA Menear, HME Duggan, S Gomez, NMB Martin, L Ruston, SL Pass, M Pass. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett 23, 1212-1216 (2013)
DOI: 10.1016/j.bmcl.2013.01.019
PMid:23375793

115. J Mateo, D Olmos, H Dumez, S Poondru, NL Samberg, S Barr, JM Van Tornout, F Jie, S Sandhu, DS Tan, V Moreno, PM LoRusso, SB Kaye, P Schoffski. A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. Br J Cancer 114, 889-896 (2016)
DOI: 10.1038/bjc.2016.59
PMid:27002938 PMCid:PMC4984800

116. AB Hall, D Newsome, Y Wang, DM Boucher, B Eustace, Y Gu, B Hare, MA Johnson, S Milton, CE Murphy, D Takemoto, C Tolman, M Wood, P Charlton, J-D Charrier, B Furey, J Golec, PM Reaper, JR Pollard. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget 5, 5674-5685 (2014)
DOI: 10.18632/oncotarget.2158
PMid:25010037 PMCid:PMC4170644

117. KM Foote, K Blades, A Cronin, S Fillery, SS Guichard, L Hassall, I Hickson, X Jacq, PJ Jewsbury, TM McGuire, JWM Nissink, R Odedra, K Page, P Perkins, A Suleman, K Tam, P Thommes, R Broadhurst, C Wood. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity. J Med Chem 56, 2125-2138 (2013)
DOI: 10.1021/jm301859s
PMid:23394205

118. FP Vendetti, A Lau, S Schamus, TP Conrads, MJ O'Connor, CJ Bakkenist. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 6, 44289-44305 (2015)
DOI: 10.18632/oncotarget.6247
PMid:26517239 PMCid:PMC4792557

119. A Peasland, L-Z Wang, E Rowling, S Kyle, T Chen, A Hopkins, WA Cliby, J Sarkaria, G Beale, RJ Edmondson, NJ Curtin. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer 105, 372-381 (2011)
DOI: 10.1038/bjc.2011.243
PMid:21730979 PMCid:PMC3172902

120. SA Dugger, A Platt, DB Goldstein. Drug development in the era of precision medicine. Nat Rev Drug Discov 17, 183-196 (2018)
DOI: 10.1038/nrd.2017.226
PMid:29217837 PMCid:PMC6287751

121. H Yang, X Jiang, B Li, HJ Yang, M Miller, A Yang, A Dhar, NP Pavletich. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368-373 (2017)
DOI: 10.1038/nature25023
PMid:29236692 PMCid:PMC5750076

122. X Chen, M Liu, Y Tian, J Li, Y Qi, D Zhao, Z Wu, M Huang, CCL Wong, H-W Wang, J Wang, H Yang, Y Xu. Cryo-EM structure of human mTOR complex 2. Cell Res 28, 518-528 (2018)
DOI: 10.1038/s41422-018-0029-3
PMid:29567957 PMCid:PMC5951902

123. CHS Aylett, E Sauer, S Imseng, D Boehringer, MN Hall, N Ban, T Maier. Architecture of human mTOR complex 1. Science 351, 48-52 (2016)
DOI: 10.1126/science.aaa3870
PMid:26678875

124. M Leone, KJ Crowell, J Chen, D Jung, GG Chiang, S Sareth, RT Abraham, M Pellecchia. The FRB domain of mTOR: NMR solution structure and inhibitor design. Biochemistry 45, 10294-10302 (2006)
DOI: 10.1021/bi060976+
PMid:16922504

125. V Veverka, T Crabbe, I Bird, G Lennie, FW Muskett, RJ Taylor, MD Carr. Structural characterization of the interaction of mTOR with phosphatidic acid and a novel class of inhibitor: compelling evidence for a central role of the FRB domain in small molecule-mediated regulation of mTOR. Oncogene 27, 585-595 (2008)
DOI: 10.1038/sj.onc.1210693
PMid:17684489

126. MS Abd Rahim, YK Cherniavskyi, DP Tieleman, SA Dames. NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated. J Biol Chem (2019)
DOI: 10.1074/jbc.RA119.007653
PMid:30867195

127. Q Rao, M Liu, Y Tian, Z Wu, Y Hao, L Song, Z Qin, C Ding, H-W Wang, J Wang; Y Xu. Cryo-EM structure of human ATR-ATRIP complex. Cell Res 28, 143-156 (2018)
DOI: 10.1038/cr.2017.158
PMid:29271416 PMCid:PMC5799817

128. X Yin, M Liu, Y Tian, J Wang, Y Xu. Cryo-EM structure of human DNA-PK holoenzyme. Cell Res 27, 1341-1350 (2017)
DOI: 10.1038/cr.2017.110
PMid:28840859 PMCid:PMC5674154

129. S Guo, J Xu, I V Pavlidis, D Lan, UT Bornscheuer, J Liu, Y Wang. Structure of product-bound SMG1 lipase: active site gating implications. FEBS J 282, 4538-4547 (2015)
DOI: 10.1111/febs.13513
PMid:26365206

Abbreviations: PIKKs: Phosphatidylinositol-3 kinase-related kinases , DNA: deoxyribonucleic acid, DDR: DNA damage response, hSMG1: Suppressor with morphological effect on genitalia family member, ATM: Ataxia telangiectasia mutated kinase, ATR: ATM- and Rad3-related kinase, DNA-PKcs: DNA dependent protein catalytic subunit, mTOR: mammalian target of rapamycin, TRRAP: Transformation-transactivation domain-associated protein, HEAT: Huntingtin, elongation factor 3 (EF3), protein phosphatase 2A (PP2A), and the yeast kinase TOR1, FAT: Frap, ATM, and TRRAP, FATC: FAT C-terminal, PRD: PIKK- regulatory domain, ATRIP: ATR interacting protein, MRN: Mre11-Rad50-Nbs1, UPF: up-frameshift, mRNA: messenger ribonucleic acid, FRAB: FKBP-rapamycin associated protein, RAFT: Rapamycin and FKBP target, mLST8: Mammalian lethal with SEC13 protein 8, NRD: Negative Regulatory Domain, FKBP12: FK506-binding protein12, FRB: FKBP12-Rapamycin-Binding (FRB) domain, HCT: Human colorectal carcinoma cell line, DSB: DNA double-strand breaks, BRCA1: Breast Cancer gene 1, Tel1: Telomere maintenance 1, EMT: Epithelial-to-Mesenchymal transition, JAK/STAT: Janus kinases/ Signal transducer and activator of transcription proteins, PD-L1: Programmed death-ligand 1, LBE: LST8-binding element, LID: LBE interacting domain, ADME: absorption, distribution, metabolism, excretion, MCM: Mini chromosomal maintenance, NHEJ: Non-homologous end joining, HR: Homologous recombination, XRCC4: X-ray repair cross-complementing protein 4, XLF: XRCC4-like factor, PNKP: Polynucleotide Kinase 3'-Phosphatase, SAF-A: Scaffold attachment factor A, hnRNP-U: Heterogeneous nuclear ribonucleoprotein U, PP6: Protein phosphatase 6, PP6R1: Protein phosphatase 6, regulatory subunit 1, siRNA: Small interfering RNA, HIV: Human Immunodeficiency Virus, GOLPH3: Golgi Phosphoprotein 3, PI3K: phosphatidylinositol 3-kinase, TIP60: Tat interactive protein, NPAT: Nuclear protein of the ATM locus, hGCN5: Histone acetyltransferase GCN5, MbII: Myc homology box II, TBP: TATA-binding protein, TFTC: TBP-free TAFII-containing complex, PCAF: P300/CBP-associated factor, HAT: Histone acetyltransferases, mdm2: Mouse double minute 2 homolog, Tra1: Transcription-associated protein 1, TPR: Tetratricopeptide, NMD: Nonsense-mediated mRNA decay, EJC: Exon junction complex, TNFα: Tumor Necrosis Factor-alpha, FLIPL: FLICE-like inhibitory protein, long form, CDK1: Cyclin dependent kinase 1

Key Words: PIKK, Phosphatidylinositol-3 kinase-related kinases, mTOR, mammalian target of rapamycin, ATR, ATM- and Rad3-related kinase, ATM, Ataxia telangiectasia mutated kinase, DNA-PKcs, DNA dependent protein catalytic subunit, TRRAP, Transformation-transactivation domain-associated protein, hSMG1, Suppressor with morphological effect on genitalia family member, DNA damage response

Send correspondence to: Vijay Thiruvenkatam, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India-382355, Tel: 91-9925907251, E-mail: vijay@iitgn.ac.in