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Damaged DNA and miscounted chromosomes: Human T cell leukemia virus type I tax oncoprotein and genetic lesions in transformed cells

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Journal of Biomedical Science

Abstract

Genetic instability is a recurring theme in human cancers. Although the molecular mechanisms mediating this effect commonly observed in transformed cells are not completely understood, it has been proposed to involve either the loss of DNA repair capabilities or the loss of chromosomal stability. The transforming retrovirus human T cell leukemia virus type I (HTLV-I) encodes a viral oncoprotein Tax, which is believed to cause the genomic instability characteristic of HTLV-I-infected cells. This review focuses on the ability of HTLV-I Tax to disrupt the cellular processes of DNA repair and chromosomal segregation. The consequences of these effects as well as the evolutionary advantage this may provide to HTLV-I are discussed.

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References

  1. Abrieu A, Magnaghi-Jaulin L, Kahana JA, Peter M, Castro A, Vigneron S, Lorca T, Cleveland DW, Labbe JC. Mps 1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell 106:83–93;2001.

    PubMed  Google Scholar 

  2. Ariumi Y, Yamaoka S, Lin JY, Hirota M, Masui O, Taya Y, Shimotohno K. HTLV-1 Tax oncoprotein represses the p53-mediated transactivation function through coactivator CBP sequestration. Oncogene 19:1491–1499;2000.

    PubMed  Google Scholar 

  3. Bishop JM. The molecular genetics of cancer. Science 235:305–311;1999.

    Google Scholar 

  4. Cereseto A, Diella F, Mulloy JC, Cara A, Michieli P, Grassmann R, Franchini G, Klotman ME. p53 functional impairment and high p21waf1/cip1 expression in human T-cell lymphotropic/leukemia virus type I-transformed T cells. Blood 88:1551–1560;1996.

    PubMed  Google Scholar 

  5. Chen RH, Shevchenko A, Mann M, Murray AW. Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J Cell Biol 143:283–295;1998.

    PubMed  Google Scholar 

  6. Chieco-Bianchi L, Saggioro D, Del Mistro A, Montaldo A, Majone F, Levis AG. Chromosome damage induced in cord blood T-lymphocytes infected in vitro by HTLV-I. Leukemia 2(12 suppl):223S-232S;1988.

    PubMed  Google Scholar 

  7. Duensing S, Munger K. Centrosome abnormalities, genomic instability and carcinogenic progression. Biochim Biophys Acta 1471:M81-M88;2001.

    PubMed  Google Scholar 

  8. Elledge SJ. Mitotic arrest: Mad2 prevents sleepy from waking up the APC. Science 279:999–1000;1998.

    PubMed  Google Scholar 

  9. Fisk HA, Winey M. The mouse Mps1p-like kinase regulates centrosome duplication. Cell 106:95–104;2001.

    Article  PubMed  Google Scholar 

  10. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH, Clevers H. Mutations in the APC tumor suppressor gene cause chromosomal instability. Nat Cell Biol 4:433–438;2001.

    Google Scholar 

  11. Franklin AA, Nyborg JK. Mechanisms of Tax regulation of human T-cell leukemia virus 1 gene expression. J Biomed Sci 2:17–29;1996.

    Google Scholar 

  12. Fujimoto T, Hatta T, Itoyama T, Nakamura H, Tsukasaki K, Yamada Y, Ikeda S, Sadamori N, Tomonaga M. High rate of chromosomal abnormalities in HTLV-I-infected T-cell colonies derived from prodromal phase of adult T-cell leukemia: A study of IL-2-stimulated colony formation in methylcellulose. Cancer Genet Cytogenet 109:1–13;1999.

    Article  PubMed  Google Scholar 

  13. Grassmann R, Dengler C, Muller-Fleckenstein I, McGuire K, Dokhelar MC, Sodroski JG, Haseltine WA. Transformation to continuous growth of primary human T lymphocytes by human T cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci USA 86:3551–3355;1989.

    Google Scholar 

  14. Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA 95:5166–5171;1998.

    Article  PubMed  Google Scholar 

  15. Heim S, Mitelman F. Cancer cytogenesis: Chromosomal and molecular genetic aberrations of tumor cells. In: Heim S, Mitelman F, eds. Cancer Cytogenetics. New York, Wiley-Liss, 1–17;1995.

    Google Scholar 

  16. Hinrichs SH, Nerenberg M, Reynolds RK, Khoury G, Jay G. A transgenic mouse model for human neurofibromatosis. Science 237:1340–1343;1987.

    PubMed  Google Scholar 

  17. Hinuma Y, Nagata K, Misoka M, Nakai T, Matsumoto T, Kiroshita K, Shirakawa S, Miyoshi I. Adult T-cell leukemia: Antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 78:6476–6480;1981.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  19. Hoyt MA, Totis L, Roberts BT.S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66:507–517;1991.

    PubMed  Google Scholar 

  20. Itoyama T, Sadamori N, Tokunaga S, Sasagawa I, Nakamura H, Yao E, Jubashi T, Yamada Y, Ikeda S, Ichimura M. Cytogenetic studies of human T-cell leukemia virus type I carriers. A family study. Cancer Genet Cytogenet 49:157–163;1990.

    Article  PubMed  Google Scholar 

  21. Jeang K-T, Widen SG, Semmes OJ, Wilson SH. HTLV-I trans-activator protein, Tax, is a trans-repressor of the human β-polymerase gene. Science 247:1082–1084;1990.

    PubMed  Google Scholar 

  22. Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 93:81–91;1998.

    Article  PubMed  Google Scholar 

  23. Kamada N, Sakurai M, Miyamoto K, Sancar A, Sadamori N, Fukuhara S, Abe S, Shiraishi Y, Abe T, Kaneko Y, Shimoyama M. Chromosome abnormalities in adult T-cell leukemia/lymphoma: A karyotype review committee report. Cancer Res 52:1482–1493;1992.

    Google Scholar 

  24. Kao S-Y, Marriott SJ. Disruption of nucleotide excision repair by the human T-cell leukemia virus type 1 Tax protein. J Virol 73:4299–4304;1999.

    PubMed  Google Scholar 

  25. Kao S-Y, Marriott SJ. Suppression of DNA repair by HTLV-I Tax is rescued by a functional p53 signaling pathway. J Biol Chem 275:35926–35931;2000.

    Article  PubMed  Google Scholar 

  26. Kasai T, Iwanaga Y, Iha H, Jeang K-T. Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. J Biol Chem 277:5187–5193;2002.

    PubMed  Google Scholar 

  27. Klein G, Klein E. Evolution of tumors and the impact of molecular oncology. Nature 315:190–195;1985.

    Article  PubMed  Google Scholar 

  28. Lemoine FJ, Kao S-Y, Marriott SJ. Suppression of DNA repair by HTLV type 1 Tax correlates with Tax trans-activation of proliferating cell nuclear antigen gene expression. AIDS Res Hum Retroviruses 16:1623–1627;2000.

    Article  PubMed  Google Scholar 

  29. Lemoine FJ, Wycuff DR, Marriott SJ. Transcriptional activity of HTLV-I Tax influences the expression of marker genes associated with cellular transformation. Dis Markers 17:129–137;2001.

    PubMed  Google Scholar 

  30. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 396:643–649;1998.

    Article  PubMed  Google Scholar 

  31. Li R, Murray AW. Feedback control of mitosis in budding yeast. Cell 66:519–531;1991.

    Article  PubMed  Google Scholar 

  32. Li R, Sonik A, Stindl R, Rasnick D, Duesberg P. Aneuploidy vs. gene mutation hypothesis of cancer: Recent study claims mutation but is found to support aneuploidy. Proc Natl Acad Sci USA 97:3236–3241;2000.

    Article  PubMed  Google Scholar 

  33. Li R, Waga S, Hannon GJ, Beach D, Stillman B. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 371:534–537;1994.

    Article  PubMed  Google Scholar 

  34. Li Y, Gorbea C, Mahaffey D, Rechsteiner M, Benezra R. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci USA 94:12431–12436;1997.

    Article  PubMed  Google Scholar 

  35. Livingston DM. Cancer chromosome defects in the colon. Nature 410:536–537;2001.

    Article  PubMed  Google Scholar 

  36. Loeb KR, Loeb LA. Significance of multiple mutations in cancer. Carcinogenesis 21:379–385;2000.

    Article  PubMed  Google Scholar 

  37. Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079;1991.

    PubMed  Google Scholar 

  38. Mahieux R, Pise-Masison CA, Lambert PF, Nicot C, De Marchis L, Gessain A, Green P, Hall W, Brady JN. Differences in the ability of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 Tax to inhibit p53 function. J Virol 74:6866–6874;2000.

    Article  PubMed  Google Scholar 

  39. Majone F, Jeang KT. Clastogenic effect of the human T-cell leukemia virus type I Tax oncoprotein correlates with unstabilized DNA breaks. J Biol Chem 275:32906–32910;2000.

    Article  PubMed  Google Scholar 

  40. Maruyama K, Fukushima T, Kawamura K, Mochizuki S. Chromosome and gene rearrangements in immortalized human lymphocytes infected with human T-lymphotropic virus type I. Cancer Res 50(17 suppl):5697S-5702S;1990.

    PubMed  Google Scholar 

  41. Miyake H, Suzuki T, Hirai H, Yoshida M. Trans-activator Tax of human T-cell leukemia virus type 1 enhances mutation frequency of the cellular genome. Virology 253:155–161;1999.

    PubMed  Google Scholar 

  42. Miyamoto K, Sato J, Kitajima K, Togawa R, Suemaru S, Sanada H, Tanaka T. Adult T-cell leukemia. Chromosome analysis of 15 cases. Cancer 52:471–478;1983.

    PubMed  Google Scholar 

  43. Mozzherin DJ, Shibutani S, Tan CK, Downey KM, Fisher PA. Proliferating cell nuclear antigen promotes DNA synthesis past template lesions by mammalian DNA polymerase δ. Proc Natl Acad Sci USA 94:6126–6131;1997.

    Article  PubMed  Google Scholar 

  44. Murphy KL, Dennis AP, Rosen JM. A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model. FASEB J 14:2291–2302;2000.

    Article  PubMed  Google Scholar 

  45. Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G. The tat gene of human T-lymphotropic virus type I induces mesenchymal tumors in transgenic mice. Science 237:1324–1329;1987.

    PubMed  Google Scholar 

  46. Okamoto T, Ohno Y, Tsugane S, Watanabe S, Shimoyama M, Tajima K, Miwa M, Shimotohno K. Multi-step carcinogenesis model for adult T-cell leukemia. Jpn J Can Res 80:191–195;1989.

    Google Scholar 

  47. Perucho M. Cancer of the microsatellite mutator phenotype. Biol Chem 377:677–684;1996.

    Google Scholar 

  48. Philpott SM, Buehring GC. Defective DNA repair in cells with human T-cell leukemia bovine leukemia viruses: Role of tax gene. J Natl Cancer Inst 91:933–942;1999.

    Article  PubMed  Google Scholar 

  49. Pise-Masison CA, Choi KS, Radonovich M, Dittmer J, Kim SJ, Brady JN. Inhibition of p53 transactivation function by the human T-cell lymphotropic virus type 1 Tax protein. J Virol 72:1165–1170;1998.

    PubMed  Google Scholar 

  50. Pise-Masison CA, Mahieux R, Jiang H, Ashcroft M, Radonovich M, Duvall J, Guillerm C, Brady JN. Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-κB pathway and is dependent on p53 phosphorylation. Mol Cell Biol 20:3377–3386;2000.

    Article  PubMed  Google Scholar 

  51. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419;1980.

    PubMed  Google Scholar 

  52. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B. A model for p53 induced apoptosis. Nature 389:300–305;1997.

    PubMed  Google Scholar 

  53. Pozzati R, Vogel J, Jay G. The human T lymphotropic virus I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol Cell Biol 10:413–417;1990.

    PubMed  Google Scholar 

  54. Ressler S, Connor LM, Marriott SJ. Cellular transformation by human T-cell leukemia virus type I. FEMS Microbiol Lett 140:99–109;1996.

    Article  Google Scholar 

  55. Rowley JD, Haren JM, Wong-Staal F, Franchini G, Gallo RC, Blattner W. Chromosome patterns in cells from patients positive for human T-cell leukemia/lymphoma virus. In: Gallo RC, Essex ME, Gross L, eds. Human T-Cell Leukemia/Lymphoma Virus. New York, Cold Spring Harbor Laboratory, 85–89;1984.

    Google Scholar 

  56. Sadamori N. Cytogenetic implication in adult T-cell leukemia. A hypothesis of leukemogenesis. Cancer Genet Cytogenet 51:131–136;1991.

    Article  PubMed  Google Scholar 

  57. Saggioro D, Majone F, Forino M, Turchetto L, Leszl A, Chieco-Bianchi L. Tax protein of human T-lymphotropic virus type I triggers DNA damage. Leuk Lymphoma 12:281–286;1994.

    PubMed  Google Scholar 

  58. Sen S. Aneuploidy and cancer. Curr Opin Oncol 12:82–88;2000.

    Article  PubMed  Google Scholar 

  59. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br J Haematol 79:428–437;1991.

    PubMed  Google Scholar 

  60. Suzuki T, Kitao S, Matsushime H, Yoshida M. HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. EMBO J 15:1607–1614;1996.

    PubMed  Google Scholar 

  61. Suzuki T, Narita T, Uchida-Toita M, Yoshida M. Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by Tax protein of HTLV-1 through two distinct mechanisms. Virology 259:384–391;1999.

    Article  PubMed  Google Scholar 

  62. Suzuki T, Uchida-Toita M, Yoshida M. Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site. Oncogene 18:4137–4143;1999.

    Article  PubMed  Google Scholar 

  63. Tanaka A, Takahashi G, Yamaoka S, Nosaka T, Maki M, Hatanaka M. Oncogenic transformation by thetax gene of human T cell leukemia virus type I in vitro. Proc Natl Acad Sci USA 87:1071–1075;1990.

    PubMed  Google Scholar 

  64. Ueshima Y, Fukuhara S, Hattori T, Uchiyama T, Takatsuki K, Uchino H. Chromosome studies in adult T-cell leukemia in Japan: Significance of trisomy 7. Blood 58:420–425;1981.

    PubMed  Google Scholar 

  65. Van PL, Yim KW, Jin DY, Dapolito G, Kurimasa A, Jeang KT. Genetic evidence of a role for ATM in functional interaction between human T-cell leukemia virus type 1 Tax and p53. J Virol 75:396–407;2001.

    Article  PubMed  Google Scholar 

  66. Van Orden K, Giebler HA, Lemasson I, Gonzales M, Nyborg JK. Binding of p53 to the KIX domain of CREB binding protein. A potential link to human T-cell leukemia virus type I-associated leukemogenesis. J Biol Chem 274:26321–26328;1999.

    Article  PubMed  Google Scholar 

  67. Waga S, Stillman B. Anatomy of a DNA replication fork revealed by reconstitution of SV40 DNA replication in vitro. Nature 369:207–212;1994.

    Article  PubMed  Google Scholar 

  68. Wassmann K, Benezra R. Mad2 transiently associates with an APC/p55Cdc complex during mitosis. Proc Natl Acad Sci USA 95:11193–11198;1998.

    Article  PubMed  Google Scholar 

  69. Wassmann K, Benezra R. Mitotic checkpoints: From yeast to cancer. Curr Opin Genet Dev 11:83–90;2001.

    Article  PubMed  Google Scholar 

  70. Whang-Peng J, Bunn PA, Knutsen T, Kao-Shan CS, Broder S, Jaffe ES, Gelman E, Blattner W, Lofters W, Young RC, Gallo RC. Cytogenetic studies in human T-cell lymphoma virus (HTLV)-positive leukemia-lymphoma in the United States. J Natl Cancer Inst 74:357–369;1985.

    PubMed  Google Scholar 

  71. Williams N. Evolutionary lessons for cancer biology. Curr Biol 11:631–632;2001.

    Article  PubMed  Google Scholar 

  72. Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its importance in the disease. Proc Natl Acad Sci USA 79:2031–2035;1982.

    PubMed  Google Scholar 

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Marriott, S.J., Lemoine, F.J. & Jeang, KT. Damaged DNA and miscounted chromosomes: Human T cell leukemia virus type I tax oncoprotein and genetic lesions in transformed cells. J Biomed Sci 9, 292–298 (2002). https://doi.org/10.1007/BF02256583

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