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The DNA damage-induced cell death response: a roadmap to kill cancer cells

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Abstract

Upon massive DNA damage cells fail to undergo productive DNA repair and trigger the cell death response. Resistance to cell death is linked to cellular transformation and carcinogenesis as well as radio- and chemoresistance, making the underlying signaling pathways a promising target for therapeutic intervention. Diverse DNA damage-induced cell death pathways are operative in mammalian cells and finally culminate in the induction of programmed cell death via activation of apoptosis or necroptosis. These signaling routes affect nuclear, mitochondria- and plasma membrane-associated key molecules to activate the apoptotic or necroptotic response. In this review, we highlight the main signaling pathways, molecular players and mechanisms guiding the DNA damage-induced cell death response.

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Abbreviations

ATM:

Ataxia-telangiectasia mutated

ATR:

ATM and Rad3-related

Chk1:

Checkpoint kinase 1

Chk2:

Checkpoint kinase 2

DDR:

DNA damage response

DSB:

Double-strand break

γH2AX:

H2AX phosphorylated at Ser139

HIPK2:

Homeodomain-interacting protein kinase 2

IR:

Ionizing radiation

MLKL:

Mixed-lineage kinase like

MOMP:

Mitochondrial outer membrane permeabilization

PIDD:

p53-induced death domain containing protein

PML:

Promyelocytic leukemia

RIPK3:

Receptor-interacting protein kinase 3

Siah-1:

Seven in absentia homologue 1

SSB:

Single-strand break

UV:

Ultraviolet

Yap1:

Yes-associated protein 1

References

  1. Atamna H, Cheung I, Ames BN (2000) A method for detecting abasic sites in living cells: age-dependent changes in base excision repair. Proc Natl Acad Sci USA 97:686–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hoeijmakers JH (2009) DNA damage, aging, and cancer. New Engl J Med 361:1475–1485

    Article  CAS  PubMed  Google Scholar 

  3. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McKinnon PJ (2004) ATM and ataxia telangiectasia. EMBO Rep 5:772–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Klingseisen A, Jackson AP (2011) Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev 25:2011–2024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14:197–210

    Article  CAS  Google Scholar 

  8. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355

    Article  CAS  PubMed  Google Scholar 

  9. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET (2012) Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Med 18:1639–1642

    Article  PubMed  CAS  Google Scholar 

  10. Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Disc 4:307–320

    Article  CAS  Google Scholar 

  11. Panier S, Durocher D (2013) Push back to respond better: regulatory inhibition of the DNA double-strand break response. Nat Rev Mol Cell Biol 14:661–672

    Article  CAS  PubMed  Google Scholar 

  12. Jackson SP, Durocher D (2013) Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 49:795–807

    Article  CAS  PubMed  Google Scholar 

  13. Jeggo PA, Lobrich M (2015) How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability. Biochem J 471:1–11

    Article  CAS  PubMed  Google Scholar 

  14. Oh J, Lee YD, Wagers AJ (2014) Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature Med 20:870–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Burton DG, Faragher RG (2015) Cellular senescence: from growth arrest to immunogenic conversion. Age 37:27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486

    Article  CAS  PubMed  Google Scholar 

  17. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y et al (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160–1166

    Article  CAS  PubMed  Google Scholar 

  18. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA (2008) ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 31:167–177

    Article  CAS  PubMed  Google Scholar 

  19. Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC, Lukas J, Bekker-Jensen S, Bartek J, Shiloh Y (2006) Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 8:870–876

    Article  CAS  PubMed  Google Scholar 

  20. Bakr A, Oing C, Kocher S, Borgmann K, Dornreiter I, Petersen C, Dikomey E, Mansour WY (2015) Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation. Nuc Acid Res 43:3154–3166

    Article  CAS  Google Scholar 

  21. Davis AJ, Chen BP, Chen DJ (2014) DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair 17:21–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harbor Perspect Biol 5:1–14

    Article  CAS  Google Scholar 

  23. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8:37–45

    Article  CAS  PubMed  Google Scholar 

  24. Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O (2006) ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med 203:297–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Riedl SJ, Salvesen GS (2007) The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 8:405–413

    Article  CAS  PubMed  Google Scholar 

  26. Janssens S, Tinel A (2012) The PIDDosome, DNA-damage-induced apoptosis and beyond. Cell Death Differ 19:13–20

    Article  CAS  PubMed  Google Scholar 

  27. Kumar S (2009) Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? Nat Rev Cancer 9:897–903

    Article  CAS  PubMed  Google Scholar 

  28. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

    Article  CAS  PubMed  Google Scholar 

  29. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  CAS  PubMed  Google Scholar 

  30. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632

    Article  CAS  PubMed  Google Scholar 

  31. Fuchs Y, Steller H (2015) Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol 16:329–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811

    Article  CAS  PubMed  Google Scholar 

  33. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15:135–147

    Article  CAS  PubMed  Google Scholar 

  34. Silke J, Rickard JA, Gerlic M (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nature Immunol 16:689–697

    Article  CAS  Google Scholar 

  35. Linkermann A, Green DR (2014) Necroptosis. New Engl J Med 370:455–465

    Article  CAS  PubMed  Google Scholar 

  36. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714

    Article  CAS  PubMed  Google Scholar 

  37. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature immunol 1:489–495

    Article  CAS  Google Scholar 

  38. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137:1100–1111

    Article  CAS  PubMed  Google Scholar 

  39. Vercammen D, Brouckaert G, Denecker G, Van de Craen M, Declercq W, Fiers W, Vandenabeele P (1998) Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J Exp Med 188:919–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL et al (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430:694–699

    Article  CAS  PubMed  Google Scholar 

  41. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (1999) The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398:252–256

    Article  CAS  PubMed  Google Scholar 

  42. Moquin DM, McQuade T, Chan FK (2013) CYLD deubiquitinates RIP1 in the TNFalpha-induced necrosome to facilitate kinase activation and programmed necrosis. PLoS ONE 8:e76841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nature Immunol 10:348–355

    Article  CAS  Google Scholar 

  44. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131:669–681

    Article  CAS  PubMed  Google Scholar 

  45. Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, Shiba T, Yang X, Yeh WC, Mak TW et al (2008) Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nature Immunol 9:1371–1378

    Article  CAS  Google Scholar 

  46. Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI et al (2013) The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39:443–453

    Article  CAS  PubMed  Google Scholar 

  47. Rodriguez DA, Weinlich R, Brown S, Guy C, Fitzgerald P, Dillon CP, Oberst A, Quarato G, Low J, Cripps JG et al (2015) Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ 23:76–88

    Article  PubMed  CAS  Google Scholar 

  48. Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (2014) Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell 54:133–146

    Article  CAS  PubMed  Google Scholar 

  49. Upton JW, Kaiser WJ, Mocarski ES (2012) DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11:290–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. He S, Liang Y, Shao F, Wang X (2011) Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Scie USA 108:20054–20059

    Article  CAS  Google Scholar 

  51. Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517:311–320

    Article  CAS  PubMed  Google Scholar 

  52. Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, Kim SI, Kim SJ, Son MK, Hong SS et al (2015) Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res 25:707–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roos WP, Kaina B (2013) DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett 332:237–248

    Article  CAS  PubMed  Google Scholar 

  54. Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    Article  CAS  PubMed  Google Scholar 

  56. Vousden KH, Prives C (2009) Blinded by the Light: the Growing Complexity of p53. Cell 137:413–431

    Article  CAS  PubMed  Google Scholar 

  57. Weinberg RL, Veprintsev DB, Bycroft M, Fersht AR (2005) Comparative binding of p53 to its promoter and DNA recognition elements. J Mol Biol 348:589–596

    Article  CAS  PubMed  Google Scholar 

  58. Horvath MM, Wang X, Resnick MA, Bell DA (2007) Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS Genet 3:e127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Jegga AG, Inga A, Menendez D, Aronow BJ, Resnick MA (2008) Functional evolution of the p53 regulatory network through its target response elements. Proc Natl Acad Sci USA 105:944–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cui F, Zhurkin VB (2014) Rotational positioning of nucleosomes facilitates selective binding of p53 to response elements associated with cell cycle arrest. Nuc Acid Res 42:836–847

    Article  CAS  Google Scholar 

  61. Oren M (2003) Decision making by p53: life, death and cancer. Cell Death Differ 10:431–442

    Article  CAS  PubMed  Google Scholar 

  62. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    Article  CAS  PubMed  Google Scholar 

  63. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014

    Article  CAS  PubMed  Google Scholar 

  64. Chipuk JE, Bouchier-Hayes L, Green DR (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–1402

    Article  CAS  PubMed  Google Scholar 

  65. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577–590

    Article  CAS  PubMed  Google Scholar 

  66. Brooks CL, Gu W (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell 21:307–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bode AM, Dong Z (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4:793–805

    Article  CAS  PubMed  Google Scholar 

  68. Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149:1536–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  CAS  PubMed  Google Scholar 

  70. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y et al (2000) p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102:849–862

    Article  CAS  PubMed  Google Scholar 

  71. Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W, Will H, Schmitz ML (2002) Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 4:1–10

    Article  CAS  PubMed  Google Scholar 

  72. D’Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G et al (2002) Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 4:11–19

    Article  PubMed  CAS  Google Scholar 

  73. Dauth I, Kruger J, Hofmann TG (2007) Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. Cancer Res 67:2274–2279

    Article  CAS  PubMed  Google Scholar 

  74. Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K (2007) DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell 25:725–738

    Article  CAS  PubMed  Google Scholar 

  75. Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D’Orazi G (2004) Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. Exp Cell Res 293:311–320

    Article  PubMed  CAS  Google Scholar 

  76. Bitomsky N, Conrad E, Moritz C, Polonio-Vallon T, Sombroek D, Schultheiss K, Glas C, Greiner V, Herbel C, Mantovani F et al (2013) Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci USA 110:E4203–E4212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y (2001) p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol Cell 8:85–94

    Article  CAS  PubMed  Google Scholar 

  78. Ichwan SJ, Yamada S, Sumrejkanchanakij P, Ibrahim-Auerkari E, Eto K, Ikeda MA (2006) Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells. Oncogene 25:1216–1224

    Article  CAS  PubMed  Google Scholar 

  79. Li X, Dumont P, Della Pietra A, Shetler C, Murphy ME (2005) The codon 47 polymorphism in p53 is functionally significant. J Biol Chem 280:24245–24251

    Article  CAS  PubMed  Google Scholar 

  80. Okoshi R, Ozaki T, Yamamoto H, Ando K, Koida N, Ono S, Koda T, Kamijo T, Nakagawara A, Kizaki H (2008) Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J Biol Chem 283:3979–3987

    Article  CAS  PubMed  Google Scholar 

  81. Kodama M, Otsubo C, Hirota T, Yokota J, Enari M, Taya Y (2010) Requirement of ATM for rapid p53 phosphorylation at Ser46 without Ser/Thr-Gln sequences. Mol Cell Biol 30:1620–1633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yoshida K, Liu H, Miki Y (2006) Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage. J Biol Chem 281:5734–5740

    Article  CAS  PubMed  Google Scholar 

  83. Bitomsky N, Hofmann TG (2009) Apoptosis and autophagy: regulation of apoptosis by DNA damage signalling—roles of p53, p73 and HIPK2. FEBS J 276:6074–6083

    Article  CAS  PubMed  Google Scholar 

  84. Polonio-Vallon T, Kruger D, Hofmann TG (2014) ShaPINg cell fate upon DNA damage: role of Pin1 isomerase in DNA damage-induced cell death and repair. Front Oncol 4:148

    Article  PubMed  PubMed Central  Google Scholar 

  85. Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S, Ronai Z, Blandino G, Schneider C, Del Sal G (2002) The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419:853–857

    Article  CAS  PubMed  Google Scholar 

  86. Zheng H, You H, Zhou XZ, Murray SA, Uchida T, Wulf GM, Gu L, Tang X, Lu KP, Xiao ZX (2002) The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419:849–853

    Article  CAS  PubMed  Google Scholar 

  87. Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP (2002) Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J Biol Chem 277:47976–47979

    Article  CAS  PubMed  Google Scholar 

  88. Grison A, Mantovani F, Comel A, Agostoni E, Gustincich S, Persichetti F, Del Sal G (2011) Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin. Proc Natl Acad Sci USA 108:17979–17984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sorrentino G, Mioni M, Giorgi C, Ruggeri N, Pinton P, Moll U, Mantovani F, Del Sal G (2013) The prolyl-isomerase Pin1 activates the mitochondrial death program of p53. Cell Death Differ 20:198–208

    Article  CAS  PubMed  Google Scholar 

  90. Follis AV, Llambi F, Merritt P, Chipuk JE, Green DR, Kriwacki RW (2015) Pin1-induced proline isomerization in cytosolic p53 mediates BAX activation and apoptosis. Mol Cell 59:677–684

    Article  CAS  PubMed  Google Scholar 

  91. Hofmann TG, Glas C, Bitomsky N (2013) HIPK2: a tumour suppressor that controls DNA damage-induced cell fate and cytokinesis. BioEssays 35:55–64

    Article  CAS  PubMed  Google Scholar 

  92. Sombroek D, Hofmann TG (2009) How cells switch HIPK2 on and off. Cell Death Differ 16:187–194

    Article  CAS  PubMed  Google Scholar 

  93. Saul VV, Schmitz ML (2013) Posttranslational modifications regulate HIPK2, a driver of proliferative diseases. J Mol Med 91:1051–1058

    Article  CAS  PubMed  Google Scholar 

  94. D’Orazi G, Rinaldo C, Soddu S (2012) Updates on HIPK2: a resourceful oncosuppressor for clearing cancer. J Exp Clin Cancer Res 31:63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Moller A, Sirma H, Hofmann TG, Rueffer S, Klimczak E, Droge W, Will H, Schmitz ML (2003) PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 63:4310–4314

    PubMed  Google Scholar 

  96. Moller A, Sirma H, Hofmann TG, Staege H, Gresko E, Ludi KS, Klimczak E, Droge W, Will H, Schmitz ML (2003) Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression. Oncogene 22:8731–8737

    Article  PubMed  CAS  Google Scholar 

  97. Siepi F, Gatti V, Camerini S, Crescenzi M, Soddu S (2013) HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation. Biochim Biophys Acta 1833:1443–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Saul VV, de la Vega L, Milanovic M, Kruger M, Braun T, Fritz-Wolf K, Becker K, Schmitz ML (2013) HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop. J Mol Cell Biol 5:27–38

    Article  CAS  PubMed  Google Scholar 

  99. de la Vega L, Grishina I, Moreno R, Kruger M, Braun T, Schmitz ML (2012) A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress. Mol Cell 46:472–483

    Article  PubMed  CAS  Google Scholar 

  100. Hofmann TG, Jaffray E, Stollberg N, Hay RT, Will H (2005) Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification. J Biol Chem 280:29224–29232

    Article  CAS  PubMed  Google Scholar 

  101. Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG (2008) Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat Cell Biol 10:812–824

    Article  CAS  PubMed  Google Scholar 

  102. Choi DW, Seo YM, Kim EA, Sung KS, Ahn JW, Park SJ, Lee SR, Choi CY (2008) Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1. J Biol Chem 283:4682–4689

    Article  CAS  PubMed  Google Scholar 

  103. Kim SY, Choi DW, Kim EA, Choi CY (2009) Stabilization of HIPK2 by escape from proteasomal degradation mediated by the E3 ubiquitin ligase Siah1. Cancer Lett 279:177–184

    Article  CAS  PubMed  Google Scholar 

  104. Crone J, Glas C, Schultheiss K, Moehlenbrink J, Krieghoff-Henning E, Hofmann TG (2011) Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer Res 71:2350–2359

    Article  CAS  PubMed  Google Scholar 

  105. Gresko E, Roscic A, Ritterhoff S, Vichalkovski A, Del Sal G, Schmitz ML (2006) Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2. EMBO J 25:1883–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH (2003) Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115:177–186

    Article  CAS  PubMed  Google Scholar 

  107. Polonio-Vallon T, Kirkpatrick J, Krijgsveld J, Hofmann TG (2014) Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization. Cell Cycle 13:115–125

    Article  CAS  PubMed  Google Scholar 

  108. Muschik D, Braspenning-Wesch I, Stockfleth E, Rosl F, Hofmann TG, Nindl I (2011) Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2. PLoS ONE 6:e27655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Reuven N, Adler J, Porat Z, Polonio-Vallon T, Hofmann TG, Shaul Y (2015) The tyrosine kinase c-Abl promotes homeodomain-interacting protein kinase 2 (HIPK2) accumulation and activation in response to DNA damage. J Biol Chem 290:16478–16488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ (2003) TP53INP1 s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. J Biol Chem 278:37722–37729

    Article  CAS  PubMed  Google Scholar 

  111. Rui Y, Xu Z, Lin S, Li Q, Rui H, Luo W, Zhou HM, Cheung PY, Wu Z, Ye Z et al (2004) Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. EMBO J 23:4583–4594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hofmann TG, Stollberg N, Schmitz ML, Will H (2003) HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer Res 63:8271–8277

    CAS  PubMed  Google Scholar 

  113. Li Q, Wang X, Wu X, Rui Y, Liu W, Wang J, Wang X, Liou YC, Ye Z, Lin SC (2007) Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res 67:66–74

    Article  CAS  PubMed  Google Scholar 

  114. Li Q, Lin S, Wang X, Lian G, Lu Z, Guo H, Ruan K, Wang Y, Ye Z, Han J et al (2009) Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nat Cell Biol 11:1128–1134

    Article  CAS  PubMed  Google Scholar 

  115. Chung YM, Park SH, Tsai WB, Wang SY, Ikeda MA, Berek JS, Chen DJ, Hu MC (2012) FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage. Nat Comm 3:1000

    Article  CAS  Google Scholar 

  116. Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG (2000) Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70:113–122

    Article  CAS  PubMed  Google Scholar 

  117. Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG (2001) Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 3:128–133

    Article  CAS  PubMed  Google Scholar 

  118. Zou B, Chim CS, Pang R, Zeng H, Dai Y, Zhang R, Lam CS, Tan VP, Hung IF, Lan HY et al (2012) XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. Mol Carcinogen 51:422–432

    Article  CAS  Google Scholar 

  119. Lee MG, Han J, Jeong SI, Her NG, Lee JH, Ha TK, Kang MJ, Ryu BK, Chi SG (2014) XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. Proc Natl Acad Sci USA 111:15532–15537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Taira N, Yamaguchi T, Kimura J, Lu ZG, Fukuda S, Higashiyama S, Ono M, Yoshida K (2014) Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage. Proc Natl Acad Sci USA 111:717–722

    Article  CAS  PubMed  Google Scholar 

  121. Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K (2009) Modulation of microRNA processing by p53. Nature 460:529–533

    Article  CAS  PubMed  Google Scholar 

  122. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26:731–743

    Article  CAS  PubMed  Google Scholar 

  125. Zhang X, Wan G, Berger FG, He X, Lu X (2011) The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell 41:371–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    Article  CAS  PubMed  Google Scholar 

  127. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20:2202–2207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. He L, He X, Lowe SW, Hannon GJ (2007) MicroRNAs join the p53 network-another piece in the tumour-suppression puzzle. Nat Rev Cancer 7:819–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schickel R, Boyerinas B, Park SM, Peter ME (2008) MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27:5959–5974

    Article  CAS  PubMed  Google Scholar 

  130. Hofmann TG, Will H (2003) Body language: the function of PML nuclear bodies in apoptosis regulation. Cell Death Differ 10:1290–1299

    Article  CAS  PubMed  Google Scholar 

  131. Krieghoff-Henning E, Hofmann TG (2008) Role of nuclear bodies in apoptosis signalling. Biochim Biophys Acta 1783:2185–2194

    Article  CAS  PubMed  Google Scholar 

  132. Bernardi R, Papa A, Pandolfi PP (2008) Regulation of apoptosis by PML and the PML-NBs. Oncogene 27:6299–6312

    Article  CAS  PubMed  Google Scholar 

  133. Salomoni P, Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108:165–170

    Article  CAS  PubMed  Google Scholar 

  134. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP et al (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406:207–210

    Article  CAS  PubMed  Google Scholar 

  135. Gostissa M, Hofmann TG, Will H, Del Sal G (2003) Regulation of p53 functions: let’s meet at the nuclear bodies. Curr Opin Cell Biol 15:351–357

    Article  CAS  PubMed  Google Scholar 

  136. Dellaire G, Bazett-Jones DP (2007) Beyond repair foci: subnuclear domains and the cellular response to DNA damage. Cell Cycle 6:1864–1872

    Article  CAS  PubMed  Google Scholar 

  137. Conrad E, Polonio-Vallon T, Meister M, Matt S, Bitomsky N, Herbel C, Liebl M, Greiner V, Kriznik B, Schumacher S et al (2016) HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism. Cell Death Differ 23:110–122

    Article  CAS  PubMed  Google Scholar 

  138. Melino G (2003) p73, the “assistant” guardian of the genome? Ann N Y Acad Sci 1010:9–15

    Article  CAS  PubMed  Google Scholar 

  139. Conforti F, Sayan AE, Sreekumar R, Sayan BS (2012) Regulation of p73 activity by post-translational modifications. Cell Death Dis 3:e285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Allocati N, Di Ilio C, De Laurenzi V (2012) p63/p73 in the control of cell cycle and cell death. Exp Cell Res 318:1285–1290

    Article  CAS  PubMed  Google Scholar 

  141. Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G, Melino G (2005) The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J 24:836–848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Flinterman M, Guelen L, Ezzati-Nik S, Killick R, Melino G, Tominaga K, Mymryk JS, Gaken J, Tavassoli M (2005) E1A activates transcription of p73 and Noxa to induce apoptosis. J Biol Chem 280:5945–5959

    Article  CAS  PubMed  Google Scholar 

  143. Bernassola F, Salomoni P, Oberst A, Di Como CJ, Pagano M, Melino G, Pandolfi PP (2004) Ubiquitin-dependent degradation of p73 is inhibited by PML. J Exp Med 199:1545–1557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tomasini R, Mak TW, Melino G (2008) The impact of p53 and p73 on aneuploidy and cancer. Trends Cell Biol 18:244–252

    Article  CAS  PubMed  Google Scholar 

  145. Dotsch V, Bernassola F, Coutandin D, Candi E, Melino G (2010) p63 and p73, the ancestors of p53. Cold Spring Harbor Perspect Biol 2:a004887

    Article  CAS  Google Scholar 

  146. Agami R, Blandino G, Oren M, Shaul Y (1999) Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399:809–813

    Article  CAS  PubMed  Google Scholar 

  147. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, Wang JY (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399:806–809

    Article  CAS  PubMed  Google Scholar 

  148. Yoshida K, Yamaguchi T, Natsume T, Kufe D, Miki Y (2005) JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7:278–285

    Article  CAS  PubMed  Google Scholar 

  149. Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, Barlow C, Baltimore D, Wynshaw-Boris A, Kastan MB et al (1997) Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387:516–519

    Article  CAS  PubMed  Google Scholar 

  150. Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, Hobson K, Gatei M, Zhang N, Watters D et al (1997) Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387:520–523

    Article  CAS  PubMed  Google Scholar 

  151. Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA, Fontemaggi G, Fanciulli M, Schiltz L, Blandino G et al (2002) DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol Cell 9:175–186

    Article  CAS  PubMed  Google Scholar 

  152. Miller HL, Lee Y, Zhao J, Chong MJ, McKinnon PJ (2003) Atm and c-Abl cooperate in the response to genotoxic stress during nervous system development. Dev Brain Res 145:31–38

    Article  CAS  Google Scholar 

  153. Levy D, Adamovich Y, Reuven N, Shaul Y (2008) Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol Cell 29:350–361

    Article  CAS  PubMed  Google Scholar 

  154. Levy D, Adamovich Y, Reuven N, Shaul Y (2007) The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell Death Differ 14:743–751

    Article  CAS  PubMed  Google Scholar 

  155. Piret B, Schoonbroodt S, Piette J (1999) The ATM protein is required for sustained activation of NF-kappaB following DNA damage. Oncogene 18:2261–2271

    Article  CAS  PubMed  Google Scholar 

  156. Li N, Banin S, Ouyang H, Li GC, Courtois G, Shiloh Y, Karin M, Rotman G (2001) ATM is required for IkappaB kinase (IKKk) activation in response to DNA double strand breaks. J Biol Chem 276:8898–8903

    Article  CAS  PubMed  Google Scholar 

  157. Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S (2003) Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-κB activation by genotoxic stress. Cell 115:565–576

    Article  CAS  PubMed  Google Scholar 

  158. Biton S, Ashkenazi A (2011) NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell 145:92–103

    Article  CAS  PubMed  Google Scholar 

  159. Stilmann M, Hinz M, Arslan SC, Zimmer A, Schreiber V, Scheidereit C (2009) A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation. Mol Cell 36:365–378

    Article  CAS  PubMed  Google Scholar 

  160. Mabb AM, Wuerzberger-Davis SM, Miyamoto S (2006) PIASy mediates NEMO sumoylation and NF-κB activation in response to genotoxic stress. Nat Cell Biol 8:986–993

    Article  CAS  PubMed  Google Scholar 

  161. Wu ZH, Shi Y, Tibbetts RS, Miyamoto S (2006) Molecular linkage between the kinase ATM and NF-κB signaling in response to genotoxic stimuli. Science 311:1141–1146

    Article  CAS  PubMed  Google Scholar 

  162. Jin HS, Lee DH, Kim DH, Chung JH, Lee SJ, Lee TH (2009) cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation. Cancer Res 69:1782–1791

    Article  CAS  PubMed  Google Scholar 

  163. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, Matsumoto K, Takeuchi O, Akira S (2005) Essential function for the kinase TAK1 in innate and adaptive immune responses. Nature Immunol 6:1087–1095

    Article  CAS  Google Scholar 

  164. Wu ZH, Wong ET, Shi Y, Niu J, Chen Z, Miyamoto S, Tergaonkar V (2010) ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell 40:75–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Hinz M, Stilmann M, Arslan SC, Khanna KK, Dittmar G, Scheidereit C (2010) A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation. Mol Cell 40:63–74

    Article  CAS  PubMed  Google Scholar 

  166. Yang Y, Xia F, Hermance N, Mabb A, Simonson S, Morrissey S, Gandhi P, Munson M, Miyamoto S S, Kelliher MA (2011) A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-κB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage. Mol Cell Biol 31:2774–2786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Tinel A, Tschopp J (2004) The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304:843–846

    Article  CAS  PubMed  Google Scholar 

  168. Lassus P, Opitz-Araya X, Lazebnik Y (2002) Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297:1352–1354

    Article  CAS  PubMed  Google Scholar 

  169. Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S (2002) Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem 277:29803–29809

    Article  CAS  PubMed  Google Scholar 

  170. Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, Varmuza S, Latham KE, Flaws JA, Salter JC et al (1998) Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12:1304–1314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Ho LH, Taylor R, Dorstyn L, Cakouros D, Bouillet P, Kumar S (2009) A tumor suppressor function for caspase-2. Proc Natl Acad Sci USA 106:5336–5341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Peintner L, Dorstyn L, Kumar S, Aneichyk T, Villunger A, Manzl C (2015) The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell Death Differ 22:1803–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Dorstyn L, Puccini J, Wilson CH, Shalini S, Nicola M, Moore S, Kumar S (2012) Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability. Cell Death Differ 19:1288–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Janssens S, Tinel A, Lippens S, Tschopp J (2005) PIDD mediates NF-κB activation in response to DNA damage. Cell 123:1079–1092

    Article  CAS  PubMed  Google Scholar 

  175. Ando K, Kernan JL, Liu PH, Sanda T, Logette E, Tschopp J, Look AT, Wang J, Bouchier-Hayes L, Sidi S (2012) PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Mol Cell 47:681–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Manzl C, Fava LL, Krumschnabel G, Peintner L, Tanzer MC, Soratroi C, Bock FJ, Schuler F, Luef B, Geley S et al (2013) Death of p53-defective cells triggered by forced mitotic entry in the presence of DNA damage is not uniquely dependent on Caspase-2 or the PIDDosome. Cell Death Dis 4:e942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Geserick P, Wang J, Schilling R, Horn S, Harris PA, Bertin J, Gough PJ, Feoktistova M, Leverkus M (2015) Absence of RIPK3 predicts necroptosis resistance in malignant melanoma. Cell Death Dis 6:e1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Hayashi MT, Cesare AJ, Fitzpatrick JA, Lazzerini-Denchi E, Karlseder J (2012) A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat Struct Mol Biol 19:387–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Khoo KH, Verma CS, Lane DP (2014) Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Disc 13:217–236

    Article  CAS  Google Scholar 

  180. O’Connor MJ (2015) Targeting the DNA damage response in cancer. Mol Cell 60:547–560

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Tilman Polonio-Vallon for help with the figure design and preparation and for discussion. This work has been supported by the SFB 1036 “Cellular surveillance and damage control” funded by the Deutsche Forschungsgemeinschaft (DFG). We also want to apologize to all authors of important publication which could not be mentioned here due to focus and space limitation.

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  1. German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Sonja Matt & Thomas G. Hofmann

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Matt, S., Hofmann, T.G. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell. Mol. Life Sci. 73, 2829–2850 (2016). https://doi.org/10.1007/s00018-016-2130-4

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