Advertisement

Analysis from the perspective of cilia: the protective effect of PARP inhibitors on visual function during light-induced damage

  • Lin Che
  • Jing-Yao Song
  • Yan Lou
  • Guang-Yu LiEmail author
Review

Abstract

Purpose

To analyze the protective effect of PARP inhibitors on light-damaged retina and explore its possible mechanism from the perspective of ciliopathy.

Methods

A systematic review of the literature was performed to investigate the protection of PARP inhibition on light-damaged cilia. PubMed database was retrieved to find the relevant studies and 119 literatures were involved in the review.

Results

In retina, the outer segment of photoreceptor is regarded as a special type of primary cilium, so various retinal diseases actually belong to a type of ciliopathy. The retina is the only central nervous tissue exposed to light, but poly (ADP-ribose) polymerase (PARP), as a nuclear enzyme repairing DNA breaks, is overactivated during the light-induced DNA damage, and is involved in the cell death cascade. Studies show that both ATR and phosphorylated Akt colocalize with cilium and play an important role in regulating ciliary function. PARP may function at ATR or PI3K/Akt signal to exert protective effect on cilia.

Conclusion

PARP inhibitors may protect the cilia/OS of photoreceptor during light-induced damage, which the possible mechanism may be involved in the activation of ATR and PI3K/Akt signal.

Keywords

PARP Ciliary ATR PI3K/Akt Light-induced damage 

Notes

Funding

The study was funded by the National Natural Science Foundation of China (No. 81570864) and the Natural Science Foundation of Jilin Province (Nos. 20160101004JC; 20160414045GH; 2016J041).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Lee JE, Gleeson JG (2011) Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr Opin Neurol 24(2):98–105PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rao Damerla R, Gabriel GC, Li Y et al (2014) Role of cilia in structural birth defects: insights from ciliopathy mutant mouse models. Birth Defects Res C Embryo Today 102(2):115–125PubMedCrossRefGoogle Scholar
  3. 3.
    Otto EA, Schermer B, Obara T et al (2003) Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 34(4):413–420PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Zariwala MA, Knowles MR, Omran H (2007) Genetic defects in ciliary structure and function. Annu Rev Physiol 69:423–450PubMedCrossRefGoogle Scholar
  5. 5.
    Adams M, Smith UM, Logan CV, Johnson CA (2008) Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet 45(5):257–267PubMedCrossRefGoogle Scholar
  6. 6.
    Marshall WF (2008) The cell biological basis of ciliary disease. J Cell Biol 180(1):17–21PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gerdes JM, Davis EE, Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137(1):32–45PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hildebrandt F, Benzing T, Katsanis N (2011) Ciliopathies. N Engl J Med 364(16):1533–1543PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hosokawa Y, Miki-Noumura T (1987) Bending motion of Chlamydomonas axonemes after extrusion of central-pair microtubules. J Cell Biol 105(3):1297–1301PubMedCrossRefGoogle Scholar
  10. 10.
    Dentler WL (1980) Structures linking the tips of ciliary and flagellar microtubules to the membrane. J Cell Sci 42:207–220PubMedGoogle Scholar
  11. 11.
    Dentler WL, Pratt MM, Stephens RE (1980) Microtubule-membrane interactions in cilia. II. Photochemical cross-linking of bridge structures and the identification of a membrane-associated dynein-like ATPase. J Cell Biol 84(2):381–403PubMedCrossRefGoogle Scholar
  12. 12.
    Brokaw CJ, Kamiya R (1987) Bending patterns of Chlamydomonas flagella: IV. Mutants with defects in inner and outer dynein arms indicate differences in dynein arm function. Cell Motil Cytoskelet 8(1):68–75CrossRefGoogle Scholar
  13. 13.
    Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3(11):813–825PubMedCrossRefGoogle Scholar
  14. 14.
    Marshall WF (2010) Cilia self-organize in response to planar cell polarity and flow. Nat Cell Biol 12(4):314–315PubMedCrossRefGoogle Scholar
  15. 15.
    Fischer E, Pontoglio M (2009) Planar cell polarity and cilia. Semin Cell Dev Biol 20(8):998–1005PubMedCrossRefGoogle Scholar
  16. 16.
    Kim S, Tsiokas L (2011) Cilia and cell cycle re-entry: more than a coincidence. Cell Cycle 10(16):2683–2690PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Jackson PK (2011) Do cilia put brakes on the cell cycle? Nat Cell Biol 13(4):340–342PubMedCrossRefGoogle Scholar
  18. 18.
    Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M, Eggenschwiler JT (2010) Broad-minded links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. Dev Cell 18(2):237–247PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zhou J (2009) Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol 71:83–113PubMedCrossRefGoogle Scholar
  20. 20.
    Ishikawa H, Marshall WF (2011) Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 12(4):222–234PubMedCrossRefGoogle Scholar
  21. 21.
    Pazour GJ, Dickert BL, Vucica Y et al (2000) Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151(3):709–718PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Reiter JF, Blacque OE, Leroux MR (2012) The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 13(7):608–618PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kim S, Dynlacht BD (2013) Assembling a primary cilium. Curr Opin Cell Biol 25(4):506–511PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Graser S, Stierhof YD, Lavoie SB et al (2007) Cep164, a novel centriole appendage protein required for primary cilium formation. J Cell Biol 179(2):321–330PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Schmidt KN, Kuhns S, Neuner A, Hub B, Zentgraf H, Pereira G (2012) Cep164 mediates vesicular docking to the mother centriole during early steps of ciliogenesis. J Cell Biol 199(7):1083–1101PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Goetz SC, Liem KF Jr, Anderson KV (2012) The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell 151(4):847–858PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Tanos BE, Yang HJ, Soni R et al (2013) Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev 27(2):163–168PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kuhns S, Schmidt KN, Reymann J et al (2013) The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis. J Cell Biol 200(4):505–522PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Veleri S, Manjunath SH, Fariss RN et al (2014) Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis. Nat Commun 20(5):4207CrossRefGoogle Scholar
  30. 30.
    Inoko A, Matsuyama M, Goto H et al (2012) Trichoplein and Aurora A block aberrant primary cilia assembly in proliferating cells. J Cell Biol 197(3):391–405PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bettencourt-Dias M, Carvalho-Santos Z (2008) Double life of centrioles: CP110 in the spotlight. Trends Cell Biol 18(1):8–11PubMedCrossRefGoogle Scholar
  32. 32.
    Kobayashi T, Tsang WY, Li J, Lane W, Dynlacht BD (2011) Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis. Cell 145(6):914–925PubMedCrossRefGoogle Scholar
  33. 33.
    Huang N, Zhang D, Li F et al (2018) M-Phase Phosphoprotein 9 regulates ciliogenesis by modulating CP110-CEP97 complex localization at the mother centriole. Nat Commun. 9(1):4511PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Tsang WY, Dynlacht BD (2013) CP110 and its network of partners coordinately regulate cilia assembly. Cilia 2(1):9PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Chang B, Khanna H, Hawes N et al (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15(11):1847–1857PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Tsang WY, Bossard C, Khanna H et al (2008) CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev Cell 15(2):187–197PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kobayashi T, Kim S, Lin YC, Inoue T, Dynlacht BD (2014) The CP110-interacting proteins Talpid3 and Cep290 play overlapping and distinct roles in cilia assembly. J Cell Biol 204(2):215–229PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pan J (2008) Cilia and ciliopathies: from Chlamydomonas and beyond. Sci China C Life Sci 51(6):479–486PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Q, Pan J, Snell WJ (2006) Intraflagellar transport particles participate directly in cilium-generated signaling in Chlamydomonas. Cell 125(3):549–562PubMedCrossRefGoogle Scholar
  40. 40.
    Fliegauf M, Benzing TH (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8(11):880–893PubMedCrossRefGoogle Scholar
  41. 41.
    Sjöstrand FS (1953) The ultrastructure of the outer segments of rods and cones of the eye as revealed by the electron microscope. J Cell Physiol 42(1):15–44CrossRefGoogle Scholar
  42. 42.
    Ramamurthy V, Cayouette M (2009) Development and disease of the photoreceptor cilium. Clin Genet 76(2):137–145PubMedCrossRefGoogle Scholar
  43. 43.
    Lepanto P, Davison C, Casanova G, Badano JL, Zolessi FR (2016) Characterization of primary cilia during the differentiation of retinal ganglion cells in the zebrafish. Neural Dev 11(1):10PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Shaban H, Richter C (2002) A2E and blue light in the retina: the paradigm of age-related macular degeneration. Biol Chem. Mar-Apr 383(3–4):537–545Google Scholar
  45. 45.
    Andrews LD, Cohen AI (1979) Freeze-fracture evidence for the presence of cholesterol in particle-free patches of basal disks and the plasma membrane of retinal rod outer segments of mice and frogs. J Cell Biol 81(1):215–228PubMedCrossRefGoogle Scholar
  46. 46.
    Caldwell RB, McLaughlin BJ (1985) Freeze-fracture study of filipin binding in photoreceptor outer segments and pigment epithelium of dystrophic and normal retinas. J Comp Neurol 236(4):523–537PubMedCrossRefGoogle Scholar
  47. 47.
    Reme CE, Malnoe A, Jung HH, Wei Q, Munz K (1994) Effect of dietary fish oil on acute light-induced photoreceptor damage in the rat retina. Invest Ophthalmol Vis Sci 35(1):78–90PubMedGoogle Scholar
  48. 48.
    Wang JY, Saito M (2001) Dietary supplementation of N-3 fatty acids and hydroperoxide levels in rat retinas. Free Radic Res 35(4):367–375PubMedCrossRefGoogle Scholar
  49. 49.
    Wiegand RD, Giusto NM, Rapp LM, Anderson RE (1983) Evidence for rod outer segment lipid peroxidation following constant illumination of the rat retina. Invest Ophthalmol Vis Sci 24(10):1433–1435PubMedGoogle Scholar
  50. 50.
    Richards MJ, Nagel BA, Fliesler SJ (2006) Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res 82(3):538–541PubMedCrossRefGoogle Scholar
  51. 51.
    Sanvicens N, Gomez-Vicente V, Masip I, Messeguer A, Cotter TG (2004) Oxidative stress-induced apoptosis in retinal photoreceptor cells is mediated by calpains and caspases and blocked by the oxygen radical scavenger CR-6. J Biol Chem 279(38):39268–39278PubMedCrossRefGoogle Scholar
  52. 52.
    Edward DP, Lam TT, Shahinfar S, Li J, Tso MO (1991) Amelioration of light-induced retinal degeneration by a calcium overload blocker. Flunarizine. Arch Ophthalmol 109(4):554–562PubMedCrossRefGoogle Scholar
  53. 53.
    Hao W, Wenzel A, Obin MS et al (2002) Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat Genet 32(2):254–260PubMedCrossRefGoogle Scholar
  54. 54.
    Yuan J, Lipinski M, Degterev A (2003) Diversity in the mechanisms of neuronal cell death. Neuron 40(2):401–413PubMedCrossRefGoogle Scholar
  55. 55.
    Kishimoto N, Ohkuma H, Uyama M (1991) Detection of destruction of anionic sites in the outer blood-retinal barrier and damage caused by iron. Nippon Ganka Gakkai Zasshi 95(2):130–139PubMedGoogle Scholar
  56. 56.
    Liu B, Hunter DJ, Rooker S et al (2013) Wnt signaling promotes Muller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci 54(1):444–453PubMedCrossRefGoogle Scholar
  57. 57.
    Harada T, Harada C, Nakayama N et al (2000) Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26(2):533–541PubMedCrossRefGoogle Scholar
  58. 58.
    Fontaine V, Kinkl N, Sahel J, Dreyfus H, Hicks D (1998) Survival of purified rat photoreceptors in vitro is stimulated directly by fibroblast growth factor-2. J Neurosci Off J Soc Neurosci 18(23):9662–9672CrossRefGoogle Scholar
  59. 59.
    Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G (1987) Structural characterization and biological functions of fibroblast growth factor. Endocr Rev 8(2):95–114PubMedCrossRefGoogle Scholar
  60. 60.
    Noell WK, Walker VS, Kang BS, Berman S (1966) Retinal damage by light in rats. Invest Ophthalmol 5(5):450–473PubMedGoogle Scholar
  61. 61.
    Kaitz M, Auerbach E (1979) Action spectrum for light-induced retinal degeneration in dystrophic rats. Vision Res 19(9):1041–1044PubMedCrossRefGoogle Scholar
  62. 62.
    Williams TP, Howell WL (1983) Action spectrum of retinal light-damage in albino rats. Invest Ophthalmol Vis Sci 24(3):285–287PubMedGoogle Scholar
  63. 63.
    Peters S, Schraermeyer U (2001) Characteristics and functions of melanin in retinal pigment epithelium. Ophthalmologe 98(12):1181–1185PubMedCrossRefGoogle Scholar
  64. 64.
    Sundelin S, Wihlmark U, Nilsson SE, Brunk UT (1998) Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity. Curr Eye Res 17(8):851–857PubMedCrossRefGoogle Scholar
  65. 65.
    Powell SR, Wang P, Divald A et al (2005) Aggregates of oxidized proteins (lipofuscin) induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins. Free Radic Biol Med 38(8):1093–1101PubMedCrossRefGoogle Scholar
  66. 66.
    Szabo C, Ohshima H (1997) DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide 1(5):373–385PubMedCrossRefGoogle Scholar
  67. 67.
    Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7(7):517–528PubMedCrossRefGoogle Scholar
  68. 68.
    Hassa PO, Hottiger MO (2008) The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. 13:3046–3082PubMedCrossRefGoogle Scholar
  69. 69.
    Scott GS, Szabo C, Hooper DC (2004) Poly(ADP-ribose) polymerase activity contributes to peroxynitrite-induced spinal cord neuronal cell death in vitro. J Neurotrauma 21(9):1255–1263PubMedCrossRefGoogle Scholar
  70. 70.
    Koh DW, Dawson TM, Dawson VL (2005) Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res 52(1):5–14PubMedCrossRefGoogle Scholar
  71. 71.
    Jagtap P, Szabo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4(5):421–440PubMedCrossRefGoogle Scholar
  72. 72.
    Li GY, Fan B, Ma TH (2011) Visible light may directly induce nuclear DNA damage triggering the death pathway in RGC-5 cells. Mol Vis. 17:3279–3289PubMedPubMedCentralGoogle Scholar
  73. 73.
    Pacher P, Szabo C (2008) Role of the Peroxynitrite-Poly(ADP-Ribose) Polymerase Pathway in Human Disease. Am J Pathol 173(1):2–13PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Virág L, Szabó C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54(54):375–429PubMedCrossRefGoogle Scholar
  75. 75.
    Islam BU, Habib S, Ahmad P, Allarakha S, Moinuddin Ali A (2015) Pathophysiological role of peroxynitrite induced DNA damage in human diseases: a special focus on Poly(ADP-ribose) Polymerase (PARP). Indian J Clin Biochem. 30(4):368–385PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Aredia F, Scovassi AI (2014) Poly(ADP-ribose): a signaling molecule in different paradigms of cell death. Biochem Pharmacol 92(1):157–163PubMedCrossRefGoogle Scholar
  77. 77.
    Burkle A, Virag L (2013) Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med 34(6):1046–1065PubMedCrossRefGoogle Scholar
  78. 78.
    David KK, Andrabi SA, Dawson TM, Dawson VL (2009) Parthanatos, a messenger of death. Front Biosci (Landmark Ed) 14:1116–1128CrossRefGoogle Scholar
  79. 79.
    Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218(2):193–202PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Beneke S (2008) Poly(ADP-ribose) polymerase activity in different pathologies–the link to inflammation and infarction. Exp Gerontol 43(7):605–614PubMedCrossRefGoogle Scholar
  82. 82.
    Paquet-Durand F, Silva J, Talukdar T et al (2007) Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. J Neurosci 27(38):10311–10319PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Arango-Gonzalez B, Trifunovic D, Sahaboglu A et al (2014) Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration. PLoS ONE 9(11):e112142PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Jiao K, Sahaboglu A, Zrenner E, Ueffing M, Ekstrom PA, Paquet-Durand F (2016) Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations. Cell Death Discov 2:16040PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Sahaboglu A, Tanimoto N, Kaur J et al (2010) PARP1 gene knock-out increases resistance to retinal degeneration without affecting retinal function. PLoS ONE 5(11):e15495PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Sahaboglu A, Sharif A, Feng L, Secer E, Zrenner E, Paquet-Durand F (2017) Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: neuroprotective effects of the PARP inhibitor PJ34. PLoS ONE 12(7):e0181374PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Vidal-Gil L, Sancho-Pelluz J, Zrenner E, Oltra M, Sahaboglu A (2019) Poly ADP ribosylation and extracellular vesicle activity in rod photoreceptor degeneration. Sci Rep. 9(1):3758PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Kim H, George E, Ragland R et al (2017) Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin Cancer Res 23(12):3097–3108PubMedCrossRefGoogle Scholar
  90. 90.
    Peasland A, Wang LZ, Rowling E et al (2011) Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer 105(3):372–381PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Yazinski SA, Comaills V, Buisson R et al (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31(3):318–332PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Huehls AM, Wagner JM, Huntoon CJ, Karnitz LM (2012) Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a Poly(ADP-Ribose) polymerase inhibitor in a novel drug combination. Mol Pharmacol 82(4):767PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Ogiwara H, Ui A, Shiotani B, Zou L, Yasui A, Kohno T (2013) Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor. Carcinogenesis 34(11):2486PubMedCrossRefGoogle Scholar
  94. 94.
    Abu-Sanad A, Wang Y, Hasheminasab F et al (2015) Simultaneous inhibition of ATR and PARP sensitizes colon cancer cell lines to irinotecan. Front Pharmacol 6:147PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ (2003) ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis 24(10):1571–1580PubMedCrossRefGoogle Scholar
  96. 96.
    Lavin MF, Kozlov S (2007) DNA damage-induced signalling in ataxia-telangiectasia and related syndromes. Radiother Oncol 83(3):231–237PubMedCrossRefGoogle Scholar
  97. 97.
    O’Driscoll M (2009) Mouse models for ATR deficiency. DNA Repair (Amst) 8(11):1333–1337CrossRefGoogle Scholar
  98. 98.
    O’Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33(4):497–501PubMedCrossRefGoogle Scholar
  99. 99.
    Sivasubramaniam S, Sun X, Pan YR, Wang S, Lee EY (2008) Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Genes Dev 22(5):587–600PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Pan YR, Lee EY (2009) UV-dependent interaction between Cep164 and XPA mediates localization of Cep164 at sites of DNA damage and UV sensitivity. Cell Cycle 8(4):655–664PubMedCrossRefGoogle Scholar
  101. 101.
    Walz G (2017) Role of primary cilia in non-dividing and post-mitotic cells. Cell Tissue Res 369(1):11–25PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Valdes-Sanchez L, De la Cerda B, Diaz-Corrales FJ et al (2013) ATR localizes to the photoreceptor connecting cilium and deficiency leads to severe photoreceptor degeneration in mice. Hum Mol Genet 22(8):1507–1515PubMedCrossRefGoogle Scholar
  103. 103.
    Lempiainen H, Halazonetis TD (2009) Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J 28(20):3067–3073PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Stiff T, Walker SA, Cerosaletti K et al (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J 25(24):5775–5782PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Stiff T, Casar Tena T, O’Driscoll M, Jeggo PA, Philipp M (2016) ATR promotes cilia signalling: links to developmental impacts. Hum Mol Genet 25(8):1574–1587PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Rundle S, Bradbury A, Drew Y, Curtin NJ (2017) Targeting the ATR-CHK1 axis in cancer therapy. Cancers (Basel). 9(5):41PubMedCentralCrossRefPubMedGoogle Scholar
  107. 107.
    Jiang X, Li X, Li W, Bai H, Zhang Z (2019) PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 23(4):2303–2313PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Huntoon CJ, Flatten KS, Wahner Hendrickson AE et al (2013) ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res 73(12):3683–3691PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N, Hay N (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12(4):502–513PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Noguchi M, Hirata N, Suizu F (2014) The links between AKT and two intracellular proteolytic cascades: ubiquitination and autophagy. Biochim Biophys Acta 1846(2):342–352PubMedGoogle Scholar
  112. 112.
    Noguchi M, Ropars V, Roumestand C, Suizu F (2007) Proto-oncogene TCL1: more than just a coactivator for Akt. FASEB J 21(10):2273–2284PubMedCrossRefGoogle Scholar
  113. 113.
    Balazs V, Ferenc G, Gabor V et al (2003) Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock. Biochem Pharmacol 65(8):1373–1382CrossRefGoogle Scholar
  114. 114.
    Kalmar-Nagy K, Degrell P, Szabo A et al (2013) PARP inhibition attenuates acute kidney allograft rejection by suppressing cell death pathways and activating PI-3K-Akt cascade. PLoS ONE 8(12):e81928PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Qin WD, Liu GL, Wang J et al (2016) Poly(ADP-ribose) polymerase 1 inhibition protects cardiomyocytes from inflammation and apoptosis in diabetic cardiomyopathy. Oncotarget 7(24):35618–35631PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Curtin NJ, Szabo C (2013) Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med 34(6):1217–1256PubMedCrossRefGoogle Scholar
  117. 117.
    Onishi K, Higuchi M, Asakura T, Masuyama N, Gotoh Y (2007) The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts. Genes Cells 12(4):535–546PubMedCrossRefGoogle Scholar
  118. 118.
    Zhu D, Shi S, Wang H, Liao K (2009) Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J Cell Sci 122(Pt 15):2760–2768PubMedCrossRefGoogle Scholar
  119. 119.
    Suizu F, Hirata N, Kimura K et al (2016) Phosphorylation-dependent Akt-Inversin interaction at the basal body of primary cilia. EMBO J 35(12):1346–1363PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of OphthalmologySecond Hospital of Jilin UniversityChangchunChina
  2. 2.Department of NephropathySecond Hospital of Jilin UniversityChangchunChina

Personalised recommendations