Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress

  • Jeon, Young Joo (Department of Biochemistry, Chungnam National University School of Medicine) ;
  • Park, Jong Ho (School of Biological Sciences, College of Natural Sciences, Seoul National University) ;
  • Chung, Chin Ha (School of Biological Sciences, College of Natural Sciences, Seoul National University)
  • Received : 2017.02.21
  • Accepted : 2017.02.23
  • Published : 2017.02.28


Error-free replication and repair of DNA are pivotal to organisms for faithful transmission of their genetic information. Cells orchestrate complex signaling networks that sense and resolve DNA damage. Post-translational protein modifications by ubiquitin and ubiquitin-like proteins, including SUMO and NEDD8, are critically involved in DNA damage response (DDR) and DNA damage tolerance (DDT). The expression of interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, has recently been shown to be induced under various DNA damage conditions, such as exposure to UV, camptothecin, and doxorubicin. Here we overview the recent findings on the role of ISG15 and its conjugation to target proteins (e.g., p53,$ {\Delta}Np63{\alpha}$, and PCNA) in the control of cellular responses to genotoxic stress, such as the inhibition of cell growth and tumorigenesis.


$ {\Delta}Np63{\alpha}$;ISG15;p53;PCNA;ubiquitin


Supported by : Chungnam National University


  1. Arimoto, K., Konishi, H., and Shimotohno, K. (2008). UbcH8 regulates ubiquitin and ISG15 conjugation to RIG-I. Mol. Immunol. 45, 1078-1084.
  2. Ashcroft, M., and Vousden, K.H. (1999). Regulation of p53 stability. Oncogene 18, 7637-7643.
  3. Bergink, S., and Jentsch, S. (2009). Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458, 461-467.
  4. Bienko, M., Green, C.M., Crosetto, N., Rudolf, F., Zapart, G., Coull, B., Kannouche, P., Wider, G., Peter, M., Lehmann, A.R., et al. (2005). Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821-1824.
  5. Brown, J.S., and Jackson, S.P. (2015). Ubiquitylation, neddylation and the DNA damage response. Open Biol. 5, 150018.
  6. Carroll, D.K., Carroll, J.S., Leong, C.O., Cheng, F., Brown, M., Mills, A.A., Brugge, J.S., and Ellisen, L.W. (2006). p63 regulates an adhesion programme and cell survival in epithelial cells. Nat. Cell Biol. 8, 551-561.
  7. Dantuma, N.P., and van Attikum, H. (2016). Spatiotemporal regulation of posttranslational modifications in the DNA damage response. EMBO J. 35, 6-23.
  8. Dipple, A. (1995). DNA adducts of chemical carcinogens. Carcinogenesis 16, 437-441.
  9. el-Deiry, W.S., Harper, J.W., O'Connor, P.M., Velculescu, V.E., Canman, C.E., Jackman, J., Pietenpol, J.A., Burrell, M., Hill, D.E., Wang, Y., et al. (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 54, 1169-1174.
  10. Farrell, P.J., Broeze, R.J., and Lengyel, P. (1979). Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells. Nature 279, 523-525.
  11. Flores, E.R., Tsai, K.Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., and Jacks, T. (2002). p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416, 560-564.
  12. Frias-Staheli, N., Giannakopoulos, N.V., Kikkert, M., Taylor, S.L., Bridgen, A., Paragas, J., Richt, J.A., Rowland, R.R., Schmaljohn, C.S., Lenschow, D.J., et al. (2007). Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses. Cell Host Microbe 2, 404-416.
  13. Gentile, M., Latonen, L., and Laiho, M. (2003). Cell cycle arrest and apoptosis provoked by UV radiation-induced DNA damage are transcriptionally highly divergent responses. Nucl. Acids Res. 31, 4779-4790.
  14. Giannakopoulos, N.V., Arutyunova, E., Lai, C., Lenschow, D.J., Haas, A.L., and Virgin, H.W. (2009). ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. J. Virol. 83, 1602-1610.
  15. Green, D.R., and Kroemer, G. (2009). Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127-1130.
  16. Guo, X., Keyes, W.M., Papazoglu, C., Zuber, J., Li, W., Lowe, S.W., Vogel, H., and Mills, A.A. (2009). TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat.Cell Biol. 11, 1451-1457.
  17. Haas, A.L., Ahrens, P., Bright, P.M., and Ankel, H. (1987). Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. J. Biol. Chem. 262, 11315-11323.
  18. Harper, J.W., and Elledge, S.J. (2007). The DNA damage response: ten years after. Mol. Cell 28, 739-745.
  19. Harrison, J.C., and Haber, J.E. (2006). Surviving the breakup: the DNA damage checkpoint. Annu. Rev. Genet. 40, 209-235.
  20. Hibi, K., Trink, B., Patturajan, M., Westra, W.H., Caballero, O.L., Hill, D.E., Ratovitski, E.A., Jen, J., and Sidransky, D. (2000). AIS is an oncogene amplified in squamous cell carcinoma. Proc. Nat. Acad. Sci. USA 97, 5462-5467.
  21. Hoege, C., Pfander, B., Moldovan, G.L., Pyrowolakis, G., and Jentsch, S. (2002). RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135-141.
  22. Jackson, S.P., and Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature 461, 1071-1078.
  23. Jackson, S.P., and Durocher, D. (2013). Regulation of DNA damage responses by ubiquitin and SUMO. Mol. Cell 49, 795-807.
  24. Jentsch, S., and Pyrowolakis, G. (2000). Ubiquitin and its kin: how close are the family ties? Trends Cell Biol. 10, 335-342.
  25. Jeon, Y.J., Choi, J.S., Lee, J.Y., Yu, K.R., Kim, S.M., Ka, S.H., Oh, K.H., Kim, K.I., Zhang, D.E., Bang, O.S., et al. (2009). ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway. EMBO Rep. 10, 374-380.
  26. Jeon, Y.J., Yoo, H.M., and Chung, C.H. (2010). ISG15 and immune diseases. Biochim. Biophys. Acta 1802, 485-496.
  27. Jeon, Y.J., Jo, M.G., Yoo, H.M., Hong, S.H., Park, J.M., Ka, S.H., Oh, K.H., Seol, J.H., Jung, Y.K., and Chung, C.H. (2012). Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15. J. Clin. Inv. 122, 2622-2636.
  28. Kannouche, P.L., and Lehmann, A.R. (2004). Ubiquitination of PCNA and the polymerase switch in human cells. Cell cycle 3, 1011-1013.
  29. Kannouche, P.L., Wing, J., and Lehmann, A.R. (2004). Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol. Cell 14, 491-500.
  30. Kerscher, O., Felberbaum, R., and Hochstrasser, M. (2006). Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22, 159-180.
  31. Kim, M.J., Latham, A.G., and Krug, R.M. (2002). Human influenza viruses activate an interferon-independent transcription of cellular antiviral genes: outcome with influenza A virus is unique. Proc. Nat. Acad. Sci. USA 99, 10096-10101.
  32. Kim, K.I., Giannakopoulos, N.V., Virgin, H.W., and Zhang, D.E. (2004). Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation. Mol. Cell. Biol. 24, 9592-9600.
  33. Kim, M.J., Hwang, S.Y., Imaizumi, T., and Yoo, J.Y. (2008). Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J. Virol. 82, 1474-1483.
  34. Lai, C., Struckhoff, J.J., Schneider, J., Martinez-Sobrido, L., Wolff, T., Garcia-Sastre, A., Zhang, D.E., and Lenschow, D.J. (2009). Mice lacking the ISG15 E1 enzyme UbE1L demonstrate increased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection. J. Virol. 83, 1147-1151.
  35. Lehmann, A.R., Niimi, A., Ogi, T., Brown, S., Sabbioneda, S., Wing, J.F., Kannouche, P.L., and Green, C.M. (2007). Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair 6, 891-899.
  36. Lenschow, D.J., Lai, C., Frias-Staheli, N., Giannakopoulos, N.V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R.E., Garcia-Sastre, A., et al. (2007). IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc. Nat. Acad. Sci. USA 104, 1371-1376.
  37. Leong, C.O., Vidnovic, N., DeYoung, M.P., Sgroi, D., and Ellisen, L.W. (2007). The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J. Clin. Inv. 117, 1370-1380.
  38. Levine, A.J., Tomasini, R., McKeon, F.D., Mak, T.W., and Melino, G. (2011). The p53 family: guardians of maternal reproduction. Nat. Rev. Mol. Cell Biol. 12, 259-265.
  39. Lindahl, T., and Barnes, D.E. (2000). Repair of endogenous DNA damage. Cold Spring Harbor Symp. Quant. Biol. 65, 127-133.
  40. Lindner, H.A., Fotouhi-Ardakani, N., Lytvyn, V., Lachance, P., Sulea, T., and Menard, R. (2005). The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J. Virol. 79, 15199-15208.
  41. Liu, M., Hummer, B.T., Li, X., and Hassel, B.A. (2004). Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. J. Interferon Cytokine Res. 24, 647-654.
  42. Loeb, K.R., and Haas, A.L. (1992). The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J. Biol. Chem. 267, 7806-7813.
  43. Loeb, L.A., and Monnat, R.J., Jr. (2008). DNA polymerases and human disease. Nat. Rev. Genet. 9, 594-604.
  44. Loo, Y.M, Owen D.M., Li, K., Erickson, A.K., Johnson, C.L., Fish, P.M., Carney, D.S., Wang, T., Ishida, H., Yoneyama, M., et al. (2006). Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc. Nat. Acad. Sci. USA 103, 6001-6006
  45. Lu, G., Reinert, J.T., Pitha-Rowe, I., Okumura, A., Kellum, M., Knobeloch, K.P., Hassel, B., and Pitha, P.M. (2006). ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation. Cell. Mol. Biol. 52, 29-41.
  46. Mailand, N., Gibbs-Seymour, I., and Bekker-Jensen, S. (2013). Regulation of PCNA-protein interactions for genome stability. Nat. Rev. Mol. Cell Biol. 14, 269-282.
  47. Malakhov, M.P., Malakhova, O.A., Kim, K.I., Ritchie, K.J., and Zhang, D.E. (2002). UBP43 (USP18). specifically removes ISG15 from conjugated proteins. J. Biol. Chem. 277, 9976-9981.
  48. Malakhova, O.A., and Zhang, D.E. (2008). ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J. Biol. Chem. 283, 8783-8787.
  49. Malakhova, O., Malakhov, M., Hetherington, C., and Zhang, D.E. (2002). Lipopolysaccharide activates the expression of ISG15-specific protease UBP43 via interferon regulatory factor 3. J. Biol. Chem. 277, 14703-14711.
  50. Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F., and Kunkel, T.A. (2000). Low fidelity DNA synthesis by human DNA polymeraseeta. Nature 404, 1011-1013.
  51. Melino, G. (2011). p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Diff. 18, 1487-1499.
  52. Mills, A.A., Zheng, B., Wang, X.J., Vogel, H., Roop, D.R., and Bradley, A. (1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708-713.
  53. Miyashita, T., and Reed, J.C. (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293-299.
  54. Moldovan, G.L., Pfander, B., and Jentsch, S. (2007). PCNA, the maestro of the replication fork. Cell 129, 665-679.
  55. Nakano, K., and Vousden, K.H. (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683-694.
  56. Okumura, A., Pitha, P.M., and Harty, R.N. (2008). ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc. Nat. Acad. Sci. USA 105, 3974-3979.
  57. Oliner, J.D., Kinzler, K.W., Meltzer, P.S., George, D.L., and Vogelstein, B. (1992). Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358, 80-83.
  58. Park, J.M., Yang, S.W., Yu, K.R., Ka, S.H., Lee, S.W., Seol, J.H., Jeon, Y.J., and Chung, C.H. (2014). Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis. Mol. Cell 54, 626-638.
  59. Park, J.H., Yang, S.W., Park, J.M., Ka, S.H., Kim, J.H., Kong, Y.Y., Jeon, Y.J., Seol, J.H., and Chung, C.H. (2016). Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification. Nat. Commun. 7, 12513.
  60. Platanias, L.C. (2005). Mechanisms of type-I- and type-II-interferonmediated signalling. Nat. Rev. Immunol. 5, 375-386.
  61. Ratia, K., Pegan, S., Takayama, J., Sleeman, K., Coughlin, M., Baliji, S., Chaudhuri, R., Fu, W., Prabhakar, B.S., Johnson, M.E., et al. (2008). A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc. Nat. Acad. Sci. USA 105, 16119-16124.
  62. Reich, N., Evans, B., Levy, D., Fahey, D., Knight, E., Jr., and Darnell, J.E., Jr. (1987). Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc. Nat. Acad. Sci. USA 84, 6394-6398.
  63. Riley, T., Sontag, E., Chen, P., and Levine, A. (2008). Transcriptional control of human p53-regulated genes. Nat. Rev. Mol. Cell Biol. 9, 402-412.
  64. Roos, W.P., Thomas, A.D., and Kaina, B. (2016). DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16, 20-33.
  65. Rouse, J., and Jackson, S.P. (2002). Interfaces between the detection, signaling, and repair of DNA damage. Science 297, 547-551.
  66. Sale, J.E. (2012). Competition, collaboration and coordinationdetermining how cells bypass DNA damage. J. Cell Sci. 125, 1633-1643.
  67. Sale, J.E., Lehmann, A.R., and Woodgate, R. (2012). Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat. Rev. Mol. Cell Biol. 13, 141-152.
  68. Sarkaria, J.N., Busby, E.C., Tibbetts, R.S., Roos, P., Taya, Y., Karnitz, L.M., and Abraham, R.T. (1999). Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 59, 4375-4382.
  69. Sayan, B.S., Sayan, A.E., Yang, A.L., Aqeilan, R.I., Candi, E., Cohen, G.M., Knight, R.A., Croce, C.M., and Melino, G. (2007). Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis. Proc. Nat. Acad. Sci. USA 104, 10871-10876.
  70. Stelter, P., and Ulrich, H.D. (2003). Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188-191.
  71. Suh, E.K., Yang, A., Kettenbach, A., Bamberger, C., Michaelis, A.H., Zhu, Z., Elvin, J.A., Bronson, R.T., Crum, C.P., and McKeon, F. (2006). p63 protects the female germ line during meiotic arrest. Nature 444, 624-628.
  72. Taniguchi, T., and Takaoka, A. (2001). A weak signal for strong responses: interferon-alpha/beta revisited. Nat. Rev. Mol. Cell Biol. 2, 378-386.
  73. Ulrich, H.D., and Walden, H. (2010). Ubiquitin signalling in DNA replication and repair. Nature reviews. Mol. Cell Biol. 11, 479-489.
  74. Wong, J.J., Pung, Y.F., Sze, N.S., and Chin, K.C. (2006). HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFNinduced ISGylation of protein targets. Proc. Nat. Acad. Sci. USA 103, 10735-10740.
  75. Wu, X., Bayle, J.H., Olson, D., and Levine, A.J. (1993). The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7, 1126-1132.
  76. Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M.D., Dotsch, V., Andrews, N.C., Caput, D., and McKeon, F. (1998). p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305-316.
  77. Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R.T., Tabin, C., Sharpe, A., Caput, D., Crum, C., et al. (1999). p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714-718.
  78. Yuan, W., and Krug, R.M. (2001). Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. EMBO J. 20, 362-371.
  79. Zhao, C., Beaudenon, S.L., Kelley, M.L., Waddell, M.B., Yuan, W., Schulman, B.A., Huibregtse, J.M., and Krug, R.M. (2004). The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFNalpha/ beta-induced ubiquitin-like protein. Proc. Nat. Acad. Sci. USA 101, 7578-7582.
  80. Zhao, C., Denison, C., Huibregtse, J.M., Gygi, S., and Krug, R.M. (2005). Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc. Nat. Acad. Sci. USA 102, 10200-10205.
  81. Zhao, C., Sridharan, H., Chen, R., Baker, D.P., Wang, S., and Krug, R.M. (2016). Influenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins. Nat. Commun. 7, 12754.
  82. Zou, W., and Zhang, D.E. (2006). The interferon-inducible ubiquitinprotein isopeptide ligase (E3). EFP also functions as an ISG15 E3 ligase. J. Biol. Chem. 281, 3989-3994.

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