International Journal of Innovative Approaches in Science Research
Abbreviation: IJIASR | ISSN (Print): 2602-4810 | ISSN (Online): 2602-4535 | DOI: 10.29329/ijiasr

Review article | International Journal of Innovative Approaches in Science Research 2020, Vol. 4(4) 191-204

DNA Damage Response and Autophagy: An Exclusive Meeting in Cancer

Mehtap Kılıç Eren

pp. 191 - 204   |  DOI:

Published online: December 28, 2020  |   Number of Views: 7  |  Number of Download: 33


Healthy cells maintain genome integrity by activating a conserved DNA damage response (DDR) pathway that halts the progression of the cell cycle and activates DNA repair. Molecular disorders preventing DDR functioning properly often predispose to cancer. Therefore DDR acts as a tumor suppressor barrier. DDR often leads to not only cell cycle arrest and DNA repair, but also induces cellular senescence and apoptosis. Ultimately, “autophagy” as a self-degradation and recycling program of cellular components can be induced by DDR. In healthy cells and the initial stage of cancer, autophagy appears to have a tumor suppressor function by eliminating damaged organelles, and protein aggregates to promote genomic instability. However, in advanced tumors, autophagy s activated, particularly as a result of hypoxia and metabolic stress, to promote tumor survival under these conditions. Autophagy can also be induced by DNA damaging chemotherapy agents in tumor cells, which mostly results in resistance to conventional cancer therapies. In addition, activation of certain oncogenes in advanced tumors may promote autophagy activation and guarantee the persistence of tumors. Thus, currently development of inhibitors targeting autophagy with potential clinical use is increasing rapidly. In this review, the DDR and autophagy signaling mechanisms, as well as the interconnecting pathways of both are highlighted. Moreover, the biological consequences of the companion of these two important cellular responses in cancer are discussed.

Keywords: DNA damage response, autophagy, cancer, apoptosis, sensecence, Wip1

How to Cite this Article?

APA 6th edition
Eren, M.K. (2020). DNA Damage Response and Autophagy: An Exclusive Meeting in Cancer . International Journal of Innovative Approaches in Science Research, 4(4), 191-204. doi: 10.29329/ijiasr.2020.312.7

Eren, M. (2020). DNA Damage Response and Autophagy: An Exclusive Meeting in Cancer . International Journal of Innovative Approaches in Science Research, 4(4), pp. 191-204.

Chicago 16th edition
Eren, Mehtap Kilic (2020). "DNA Damage Response and Autophagy: An Exclusive Meeting in Cancer ". International Journal of Innovative Approaches in Science Research 4 (4):191-204. doi:10.29329/ijiasr.2020.312.7.

  1. Abedin, MJ. Wang D.  McDonnell, MA.  Lehmann U. Kelekar A. 2007, ‘Autophagy delays apoptotic death in breast cancer cells following DNA damage’. Cell Death Differ, 500-510. [Google Scholar]
  2. Amaravadi, R. Kimmelman, AC. White E. 2016, ‘Recent insights into the function of autophagy in cancer’. Genes Dev, 1913-30. [Google Scholar]
  3. Bartek, J. Lukas, J. Bartkova, J. 2007. "DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'". Cell cycle 6: 2344-2347. [Google Scholar]
  4. Bartek, J. Lukas, J. 2007. "DNA damage checkpoints: from initiation to recovery or adaptation". Current opinion in cell biology 19: 238-245. [Google Scholar]
  5. Bartkova, J. Rezaei, N. Liontos, M. Karakaidos, P. Kletsas, D. Issaeva, N. Vassiliou, LV. Kolettas, E. Niforou, K. Zoumpourlis, VC. et al. 2006. "Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints". Nature 444: 633-637. [Google Scholar]
  6. Blackford A N, Jackson S P. 2017.‘ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response’ Molecular Cell Volume 66, Issue 6, 15 June 2017, Pages 801-817 [Google Scholar]
  7. Budanov, AV. Karin, M. 2008, ‘p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling’. Cell, 451–460.  [Google Scholar]
  8. Broustas C G, H.B. Lieberman  H B. 2014. ‘DNA Damage Response Genes and the Development of Cancer Metastasis’ Radiat Res (2014) 181 (2): 111–130. [Google Scholar]
  9. Bulavin, DV. Demidov, ON. Saito, S. Kauraniemi, P. Phillips, C. Amundson, SA. Ambrosino, C. Sauter, G. Nebreda, AR. Anderson, CW. et al. 2002. "Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity". Nature genetics 31: 210-215. [Google Scholar]
  10. Castellino, RC. De Bortoli, M. Lu, X. Moon, SH. Nguyen, TA. Shepard, MA. Rao, PH. Donehower, LA. Kim, JY. 2008. "Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D". Journal of neuro-oncology 86: 245-256. [Google Scholar]
  11. Chude, CI. Amaravadi, RK. 2017, ‘Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors’. Int J Mol Sci, 18(6): 1279. [Google Scholar]
  12. Coppé, JP. Desprez, PY. Krtolica, A. Campis, j. 2014, ‘The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression’. Annu Rev Pathol.5: 99–118. [Google Scholar]
  13. Crighton, D. Wilkinson S, O'Prey J. Syed ,N. Smith, P. Harrison, PR. Gasco, M. Garrone, O. Crook, T. Ryan, KM. 2006,’ DRAM, a p53-induced modulator of autophagy, is critical for apoptosis’. Cell,(1):121-34. [Google Scholar]
  14. Czarny, P. Pawlowska, E. Warzecha, JB. Kaarniranta, K. Blasiak, J. 2015, ‘Autophagy in DNA Damage Response’. Int. J. Mol. Sci., 2641-2662. [Google Scholar]
  15. Dikic, I. Elazar, Z. 2018, ‘Mechanism and medical implications of mammalian autophagy’. Nature Reviews Molecular Cell Biology, 349–364. [Google Scholar]
  16. Eisenberg-Lerner, A. Kimchi, A. 2012, ‘PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk’. Cell Death Differ, 788–797. [Google Scholar]
  17. El-Awady, R. A., Semreen, M. H., Saber-Ayad, M. M., Cyprian, F., Menon, V., & Al-Tel, T. H. (2016). Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells. DNA repair, 37, 1-11. [Google Scholar]
  18. Eliopoulos, AG. Havaki, S. Gorgoulisr, VG. 2016, ‘DNA Damage Response and Autophagy: A Meaningful Partnership’. Front Genet, 7: 204.  [Google Scholar]
  19. Feng, Y. Zhiyuan, Ding. Klionsky, D. 2014, ‘The machinery of macroautophagy ‘.Cell Research, 24–41. [Google Scholar]
  20. Feng, Z. Hu, W. Stanchina, E. Teresky, AK. Jin, S. Lowe, S. Levine, AJ. 2007, ‘The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways’. Cancer Res, 3043–3053.  [Google Scholar]
  21. Fuku, T. Semba, S. Yutori, H. Yokozaki, H. 2007. "Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma". Pathology international 57: 566-571. [Google Scholar]
  22. Guo, J. Chen, H. Mathew, R. Fan, J. Strohecker, A. Uzunbas, G. Kamphorst, J. Chen, G. Lemons, J. Karantza, V. Hilary, A. et al.  2011, ‘Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis’. Genes Dev, 717-29. [Google Scholar]
  23. Halazonetis, TD. Gorgoulis, VG. Bartek, J. 2008, ‘An oncogene-induced DNA damage model for cancer development’. 319(5868):1352-5. [Google Scholar]
  24. Hosoya N, Miyagawa K. 2014. ‘Targeting DNA damage response in cancer therapy’ Cancer Sci 105 (2014) 370–388 [Google Scholar]
  25. Hu Feng W., Modica Z., Klimstra I., Song DS., Allen L., Brennan PJ., Levine MF., Tang AJ., LH. 2010. "Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway". Genes & cancer 1: 360-368. [Google Scholar]
  26. Kang, C. Xu, Q. Martin, TD. Li, MZ. Demaria, M. Aron, L. Lu, T. Yankner BA. Campisi J. Elledge SJ. 2015, ‘The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4’. Science, 349. [Google Scholar]
  27.   [Google Scholar]
  28. Katayama, M. Kawaguchi, T. Berger, MS. Pieper, RO. 2007, ‘DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells’. Cell Death Differ, 548-558. [Google Scholar]
  29. Kilic, M. Schmitt, CA. 2008.  Tumor senescence in cancer treatment. Part 6. Chapter III. "Exploiting drug induced senescence in transgenic mouse models" BEYOND APOPTOSIS: CELLULAR OUTCOMES OF CANCER THERAPY,. in Book "  Tumor senescence in cancer treatment. Part 6. Chapter III. "Exploiting drug induced senescence in transgenic mouse models" BEYOND APOPTOSIS: CELLULAR OUTCOMES OF CANCER THERAPY," p. 273. Informa Health Care  USA, New York. [Google Scholar]
  30. Kilic-Eren, M. Boylu, T. Tabor, V. 2013. "Targeting PI3K/Akt represses Hypoxia inducible factor-1alpha activation and sensitizes Rhabdomyosarcoma and Ewing's sarcoma cells for apoptosis". Cancer cell international 13: 36. [Google Scholar]
  31. Kleiblova, P. Shaltiel, A. Benada, J. Sevcik, J. Pechackova, S. Pohlreich, P. Voest, EE. Dundr, P. Bartek, J. Kleibl, Z. et al. 2013. "Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint". The Journal of cell biology 201: 511-521. [Google Scholar]
  32. Le Guezennec, X. Brichkina, A. Huang, YF. Kostromina, E. Han, W. Bulavin, DV. 2012, ‘Wip1-dependent regulation of autophagy, obesity, and atherosclerosis’. Cell Metab, 16(1):68-8. [Google Scholar]
  33.   [Google Scholar]
  34. Levy Mulcahy, JM. Towers, CG. Thorburn, A.2017, ‘Targeting Autophagy in Cancer’, Nat Rev Cancer, 528–542. [Google Scholar]
  35. Liang, Y., Lin, S. Y., Brunicardi, F. C., Goss, J., & Li, K. (2009). DNA damage response pathways in tumor suppression and cancer treatment. World journal of surgery, 33(4), 661-666. [Google Scholar]
  36. Lin, W. Yuan, N. Wang, Z. Cao, Y. Fang, Y. Li, X. Xu, F. Song, L. Wang, J. Zhang, H. Yan, L. Xu, L. Zhang, X. Zhang, S. 2015, ‘Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury’. Sci Rep, 5: 12362. [Google Scholar]
  37.   [Google Scholar]
  38. Lowe, J. Cha, H. Lee, MO. Mazur, SJ. Appella, E. Fornace, AJ.  2012. "Regulation of the Wip1 phosphatase and its effects on the stress response". Frontiers in bioscience 17: 1480-1498. [Google Scholar]
  39.   [Google Scholar]
  40. Lukas, J. Lukas, C. Bartek, J. 2011,’ More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance’. Nat Cell Biol., 13(10):1161-9 [Google Scholar]
  41. Ma, XH. Piao, S. Wang, D. McAfee, QW. Nathanson, KL. Lum, JJ. Li, LZ. Amaravadi, RK. 2011, ‘Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma’. Clin Cancer Res, 3478–3489. [Google Scholar]
  42. Marinković, M. Šprung, M. Buljubašić, Maja. Novak, I. 2018, ‘Autophagy Modulation in Cancer: Current Knowledge of Action and Therapy’. Oxidative Medicine and Cellular Longevity, [Google Scholar]
  43.   [Google Scholar]
  44. Medema, RH. Macurek, L. 2012. "Checkpoint control and cancer". Oncogene 31: 2601-2613. [Google Scholar]
  45. Mirzayans, R. Andrais, B. Scott, A. Wang, YW. Murray, D. 2013. "Ionizing radiation-induced responses in human cells with differing TP53 status". International journal of molecular sciences 14: 22409-22435. [Google Scholar]
  46. Morselli, E. Galluzzi, L. Kepp, O. Vicencio, J.M. Criollo, A. Maiuri, M.C. Kroemer, 2009, G. ‘Anti- and pro-tumor functions of autophagy’. Biochim. Biophys. Acta, 1524–1532. [Google Scholar]
  47. Mosieniak, G. Sliwinska, M.A. Alster, O. Strzeszewska, A. Sunderland, P. Piechota, M. Was, H. Sikora, E. 2015, ‘Polyploidy Formation in Doxorubicin-Treated Cancer Cells Can Favor Escape from Senescence’. Neoplasia, 17, 882–893. [Google Scholar]
  48.   [Google Scholar]
  49. Mosieniak, G., Sliwinska, M. A., Przybylska, D., Grabowska, W., Sunderland, P., Bielak, A., & Sikora, E. (2016). Curcumin-treated cancer cells show mitotic disturbances leading to growth arrest and induction of senescence phenotype. The International Journal of Biochemistry & Cell Biology, 74, 33-43. [Google Scholar]
  50. Olcina, M. M., Grand, R. J., & Hammond, E. M. (2014). ATM activation in hypoxia-causes and consequences. Molecular & cellular oncology, 1(1), e29903. [Google Scholar]
  51. Pietrocola F, Izzo V, Niso-Santano M, Vacchelli E, Galluzzi L, Maiuri MC, Kroemer G. Regulation of autophagy by stress-responsive transcription factors. Semin Cancer Biol. 2013 Oct;23(5):310-22. [Google Scholar]
  52. Rauta, J. Alarmo, EL. Kauraniemi, P. Karhu, R. Kuukasjarvi, T. Kallioniemi, A. 2006. "The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours". Breast cancer research and treatment 95: 257-263. [Google Scholar]
  53. Rieber, M. Rieber, MS. 2008, ‘Sensitization to radiation-induced DNA damage accelerates loss of bcl-2 and increases apoptosis and autophagy’. Cancer Biol Ther, 1561-1566. [Google Scholar]
  54.   [Google Scholar]
  55. Rodríguez-Vargas, JM. Ruiz-Magaña, MJ. Ruiz-Ruiz, C. Majuelos-Melguizo, J. Peralta-Leal, A. Rodríguez, MI. Muñoz-Gámez, JA. de Almodóvar, MR. Siles, E. Rivas, AL. Jäättela, M. Oliver, FJ. 2012, ‘ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy’. Cell Res, 1181–1198. [Google Scholar]
  56. Roos, WP.Thomas, AD. Kaina, B, 2016,’ DNA damage and the balance between survival and death in cancer biology’. Nat Rev Cancer.,16(1):20-33. [Google Scholar]
  57. Saito-Ohara, F. Imoto I. Inoue, J. Hosoi, H. Nakagawara, A. Sugimoto, T. Inazawa J. 2003. "PPM1D is a potential target for 17q gain in neuroblastoma". Cancer research 63: 1876-1883. [Google Scholar]
  58. Santana-Codina N, J. D. Mancias J D, Kimmelman A C, 2017.  ‘The Role of Autophagy in Cancer’ Annual Review of Cancer Biology’ Vol. 1:19-39 [Google Scholar]
  59. Shimada M. Nakanishi M. 2013. Response to DNA damage: why do we need to focus on protein phosphatases?’ Front. Oncol., 31 January 2013  [Google Scholar]
  60. Singh, K. Matsuyama, S. Drazba, JA. Almasan, A. 2012, ‘Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress’. Autophagy, 236–51. [Google Scholar]
  61. Song, JY. Ryu, SH. Cho, YM. Kim, YS. Lee, BM. Lee, SW. Choi, J. 2013. "Wip1 suppresses apoptotic cell death through direct dephosphorylation of BAX in response to gamma-radiation". Cell death & disease 4: e744. [Google Scholar]
  62. Stambolic, V. MacPherson, D. Sas, D. Lin, Y. Snow, B. Jang, Y. Benchimol, S. Mak, TW. 2001, ‘Regulation of PTEN transcription by p53’. Mol. Cell, 317–325. [Google Scholar]
  63.   [Google Scholar]
  64. Tan, DS. Lambros, MB. Rayter, S. Natrajan, R. Vatcheva, R. Gao, Q. Marchio, C. Geyer, FC. Savage, K. Parry, S. et al. 2009. "PPM1D is a potential therapeutic target in ovarian clear cell carcinomas". Clinical cancer research: an official journal of the American Association for Cancer Research 15: 2269-2280. [Google Scholar]
  65. Torii, S. Yoshida, T. Arakawa, S. Honda, S. Nakanishi, A. Shimizu, S. 2016, ‘Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy’. EMBO Rep, 1552-1564. [Google Scholar]
  66. White, E. 2015, ‘The role for autophagy in cancer’. J Clin Invest, 42-46. [Google Scholar]
  67. Wong PM, Feng Y, Wang J, Shi R, Jiang X. 2015, Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A Nat Commun. 27;6:8048.. [Google Scholar]
  68. Yang, S. Wang, X. Contino, G. Liesa, M. Sahin, E. Ying, H. Bause, A. Li, Y. Stommel, JM. Dell'antonio, G. Mautner, J. Tonon, G. Haigis, M. Shirihai, OS. Doglioni, C. Bardeesy, N. Kimmelman, AC. 2011, ‘Pancreatic cancers require autophagy for tumor growth’, Genes Dev, 717–729. [Google Scholar]
  69. Yu, E. Ahn, YS. Jang, SJ. Kim, MJ. Yoon, HS. Gong, G. Choi, J. 2007. "Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers". Breast cancer research and treatment 101: 269-278. [Google Scholar]