Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Epstein–Barr virus latent membrane protein 1 induces micronucleus formation, represses DNA repair and enhances sensitivity to DNA-damaging agents in human epithelial cells

Abstract

The latent membrane protein 1 (LMP1) of Epstein–Barr virus (EBV) is a viral oncogene and it is essential for the transformation of resting B cells by the virus. The protein acts as a ligand-less membrane receptor and triggers numerous cellular signaling pathways. Cellular transformation frequently has been associated with genomic instability. To investigate whether EBV LMP1 induces chromosomal aberrations, micronucleus (MN) formation was examined in LMP1-expressing epithelial cells. The expression of wild-type LMP1 enhanced both spontaneous and bleomycin-induced MN formation. MN formation may be induced by inactivation of DNA repair and, therefore, we investigated the effect of LMP1 on DNA repair, using a host cell reactivation (HCR) assay. In the HCR assay, LMP1 reduced the capacity for DNA repair of both NPC-TW01 (p53-wild-type) and H1299 (p53-deficient) cells. As reduction of DNA repair by LMP1 occurs in p53-wild-type and p53-deficient cells, it seems that LMP1 can repress DNA repair in a p53-independent manner. Inactivation of DNA repair may render cells sensitive to DNA-damaging agents. In this study, H1299 cells harboring LMP1 were shown to be more sensitive to UV and bleomycin than those with a vector control. Using various deletion mutants of EBV LMP1 to determine the regions of LMP1 required to enhance MN formation, inhibit DNA repair and sensitize cells to DNA-damaging agents, we found that the region a. a. 189–222 (located within the CTAR1 domain) was responsible for sensitizing cells to UV and bleomycin, as well as for enhancing MN formation and repressing DNA repair. Based on these results, we suggest that disruption of DNA repair by LMP-1 results in an accumulation of unrepaired DNA and consequent genomic instability, which may contribute to the oncogenesis of LMP1 in human epithelial cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Aaronson SA and Lytle CD . (1970). Nature, 228, 359–361.

  • Abrahams PJ and Van der Eb AJ . (1976). Mutat. Res., 35, 13–22.

  • Ames BN, Gold LS and Willett WC . (1995). Proc. Natl. Acad. Sci. USA, 92, 5258–5265.

  • Athas WF, Hedayati MA, Matanoski GM, Farmer ER and Grossman L . (1991). Cancer Res., 51, 5786–5793.

  • Blanco M and Devoret R . (1973). Mutat. Res., 17, 293–305.

  • Butel JS, Lee TH and Slagle BL . (1996). Trends Microbiol., 4, 119–124.

  • Capovilla A, Carmona S and Arbuthnot P . (1997). Biochem. Biophys. Res. Commun., 232, 255–260.

  • Chang Y, Cheng SD and Tsai CH . (2002). Head Neck, 24, 143–150.

  • Chen J-Y, Chen C-J, Liu M-Y, Cho S-M, Hsu M-M, Lynn T-C, Shieh T, Tu S-M, Beasley RP, Hwang L-Y, Lee H-H, Kou S-L and Yang C-S . (1989). J. Med. Virol., 27, 269–273.

  • Chen J-Y, Liu M-Y, Chen C-J, Hsu M-M, Tu S-M, Lee H-H, Kou S-L and Yang C-S . (1985). J. Med. Virol., 17, 47–49.

  • Chen J-Y, Liu M-Y, Lynn T-C and Yang C-S . (1982). Chinese J. Microbiol. Immunol., 15, 255–261.

  • Chen MR, Liu MY, Hsu SM, Fong CC, Chen CJ, Chen IH, Hsu MM, Yang CS and Chen JY . (2001). J. Med. Virol., 64, 51–57.

  • Chen YJ, Ko JY, Chen PJ, Shu CH, Hsu MT, Tsai SF and Lin CH . (1999). Gene Chromo. Cancer, 25, 169–175.

  • Cheng Y, Poulos NE, Lung ML, Hampton G, Ou B, Lerman MI and Stanbridge EJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 3042–3047.

  • Chieco-Bianchi L, Saggioro D, Del Mistro A, Montaldo A, Majone F and Levis AG . (1988). Leukemia, 2, 223S–232S.

  • Chien YC, Chen JY, Liu MY, Yang HI, Hsu MM, Chen CJ and Yang CS . (2001). N. Engl. J. Med., 345, 1877–1882.

  • Cho EY, Hildesheim A, Chen CJ, Hsu MM, H CI, Mittl BF, Levine PH, Liu MY, Chen JY, Brinton LA, Cheng YJ and Yang CS . (2003). Cancer Epidemiol. Biomarkers Prev., 12, 1100–1104.

  • Cleaver JE and Kraemer KH . (1989). The Metabolic Basis of Inherited Disease. Scrivner CR, Beaud et AL, Sly WS and Valle D (eds). McGraw-Hill Book Co. Press: New York, pp. 2949–2971.

    Google Scholar 

  • de Vries A, van Oostrom CT, Hofhuis FM, Dortant PM, Berg RJ, de Gruijl FR, Wester PW, van Kreijl CF, Capel PJ, van Steeg H and Verbeek SJ . (1995). Nature, 377, 169–173.

  • Duensing S and Munger K . (2002). Cancer Res., 62, 7075–7082.

  • Fenech M . (2002). Drug Discovery Today, 7, 1128–1137.

  • Floettmann JE, Eliopoulos AG, Jones M, Young LS and Rowe M . (1998). Oncogene, 17, 2383–2392.

  • Fujita K, Yamasaki Y, Sawada H, Izumi Y, Fukuhara S and Uchino H . (1989). Leuk. Res., 13, 535–543.

  • Gualandi G, Giselico L, Carloni M, Palitti F, Mosesso P and Alfonsi AM . (2001). Mutagenesis., 16, 203–208.

  • Gulley ML, Burton MP, Allred DC, Nicholls JM, Amin MB, Ro JY and Schneider BG . (1998). Hum. Pathol., 29, 252–259.

  • Heddle JA . (1973). Mutat. Res., 18, 187–190.

  • Henle G and Henle W . (1976). Int. J. Cancer, 17, 1–7.

  • Henle G, Henle W and Diehl V . (1968). Proc. Natl. Acad. Sci. USA, 59, 94–101.

  • Hildesheim A and Levine PH . (1993). Epidemiol. Rev., 15, 466–485.

  • Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, Shirakawa S and Miyoshi I . (1981). Proc. Natl. Acad. Sci. USA, 78, 6476–6480.

  • Hsu TY, Pai CY, Shieh SM, Cho SM, Liu MY, Chen JY and Yang CS . (1992). J. Med. Virol., 38, 214–219.

  • Huang DP, Ho JHC, Chan WK, Lau WH and Lui M . (1989). Int. J. Cancer, 43, 936–939.

  • Huang DP, Lo KW, Choi PH, Ng AY, Tsao SY, Yiu GK and Lee JC . (1991). Cancer Genet. Cytogenet., 54, 91–99.

  • Huen DS, Henderson SA, Croom-Carter D and Rowe M . (1995). Oncogene, 10, 549–560.

  • Jacob F and Wollman EL . (1953). Cold Spring Harbor Symp. Quant. Biol., 18, 101–121.

  • Kamada N, Sakurai M, Miyamoto K, Sanada I, Sadamori N, Fukuhara S, Abe S, Shiraishi Y, Abe T and Kaneko Y . (1992). Cancer Res., 52, 1481–1493.

  • Kao SY, Lemoine FJ and Mariott SJ . (2000). Oncogene, 19, 2240–2248.

  • Kao SY and Marriott SJ . (1999). J. Virol., 73, 4299–4304.

  • Klocker H, Schneider R, Burtscher HJ, Auer B, Hirsch-Kauffmann M and Schweiger M . (1986). Eur. J. Cell. Biol., 39, 346–351.

  • Lee TH, Elledge SJ and Butel JS . (1995). J. Virol., 69, 1107–1114.

  • Lehmann AR and Oomen A . (1985). Nucleic Acids Res., 13, 2087–2095.

  • Lin CS, Kuo HH, Chen JY, Yang CS and Wang WB . (2000). J. Mol. Biol., 303, 7–23.

  • Lin CT, Wong CI, Chan WY, Tzung KW, Ho JK, Hsu MM and Chuang SM . (1990). Lab. Invest., 62, 713–724.

  • Liu MY, Chang YL, Ma J, Yang HL, Hsu MM, Chen CJ, Chen JY and Yang CS . (1997). J. Med. Virol., 52, 262–269.

  • Liu MY, Cou WW, Nutter L, Hsu MM and Chen JY . (1989). J. Med. Virol., 28, 101–106.

  • Liu MY, Shih YY, Chou SP, Chen CJ, Sheen TS, Yang CS and Chen JY . (1998). J. Med. Virol., 56, 179–185.

  • Lo KW, Huang DP and Lau KM . (1995). Cancer Res., 55, 2039–2043.

  • Lo KW, Mok CH, Huang DP, Liu YX, Choi PH, Lee JC and Tsao SW . (1992). Anticancer Res., 12, 1957–1963.

  • Lu JJ, Chen JY, Hsu TY, Yu WC, Su IJ and Yang CS . (1996). J. Gen. Virol., 77, 1883–1892.

  • Lung ML, Hu Y, Cheng Y, Li MF, Tang CM, O SK and Iggo RD . (1998). Cancer Lett., 133, 89–94.

  • Lytle CD, Aaronson SA and Harvey E . (1972). Int. J. Radiat. Biol., 22, 159–165.

  • Macera MJ, Hyde P, Peddanna N, Szabo P, Gogineni SK and Verma RS . (1996). Am. J. Hematol., 52, 53–57.

  • Majone F, Semmes OJ and Jeang KT . (1993). Virology, 193, 456–459.

  • Maruyama K, Fukushima T, Kawamura K and Mochizuki S . (1990). Cancer Res., 50, 5697S–5702S.

  • Matsuoka A, Yamazaki N, Suzuki T, Hayashi M and Sofuni T . (1992). Mutat. Res., 272, 223–236.

  • Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D'Amico D, Bodner S, Oie HK, Linnoila I, Mulshine JL, Minna JD and Grazdar AF . (1992). Oncogene, 7, 171–180.

  • Old LJ, Boyse EA, Oettgen HF, de Harven E, Geering G, Williamson B and Clifford P . (1966). Proc. Natl. Acad. Sci. USA, 56, 1699–1704.

  • Parry JM and Parry EM . (1987). Mutat. Res., 181, 267–287.

  • Philpott SM and Buehring GC . (1999). J. Natl. Cancer Inst., 91, 933–942.

  • Protic-Sabljic M and Kraemer KH . (1985). Proc. Natl. Acad. Sci. USA, 82, 6622–6626.

  • Rhim JS, Jay G, Arnstein P, Price FM, Sanford KK and Aaronson SA . (1985). Science, 227, 1250–1252.

  • Rickinson AB and Kieff E . (2001). Fields' Virology, Vol. 75. Knipe DM and Howley PM (eds). Lippincott Williams & Wilkins: Philadelphia, pp. 2575–2627.

    Google Scholar 

  • Sands AT, Abuin A, Sanchez A, Conti CJ and Bradley A . (1995). Nature, 377, 162–165.

  • Shao JY, Huang XM, Yu XJ, Huang LX, Wu QL, Xia JC, Wang HY, Feng QS, Ren ZF, Ernberg I, Hu LF and Zeng YX . (2001). Anticancer Res., 21, 3021–3029.

  • Smith ML, Chen IT, Zhan Q, O'Connor PM and Fornace Jr AJ . (1995). Oncogene, 10, 1053–1059.

  • Spruck III CH, Tsai YC, Huang DP, Yang AS, Rideout III WM, Gonzalez-Zulueta M, Choi P, Lo KW, Yu MC and Jones PA . (1992). Cancer Res., 52, 4787–4790.

  • Sternes KL and Vig BK . (1989). Mutagenesis., 4, 425–431.

  • Stopper H, Full M, Helbig R and Speit G . (1997). Mutat. Res., 383, 107–112.

  • Sun Y, Hegamyer G, Cheng YJ, Hildesheim A, Chen JY, Chen IH, Cao Y, Yao KT and Colburn NH . (1992). Proc. Natl. Acad. Sci. USA, 89, 6516–6520.

  • Sun Y, Hildesheim A, Lanier AE, Cao Y, Yao KT, Raab-Traub N and Yang CS . (1995). Oncogene, 10, 785–788.

  • Thoday JM . (1951). Br. J. Radiol., 24, 572–576.

  • Tran H, Brunet A, Grenier JM, Datta SR, Fornace Jr AJ, DiStefano PS, Chiang LW and Greenberg ME . (2002). Science, 296, 530–534.

  • Tsujimoto Y . (1989). Proc. Natl. Acad. Sci. USA, 86, 1958–1962.

  • Van der Eb SA and Cohen JA . (1967). Biochem. Biophys. Res. Commun., 28, 284–288.

  • Zeng Y, Zhang LG, Li HY, Jan MG, Zhang Q, Wu YC, Wang YS and Su GR . (1982). Int. J. Cancer, 29, 139–141.

Download references

Acknowledgements

We are indebted to Dr Tim J Harrison at Royal Free and University College Medical School, University College London for critically reading the manuscript. This work was supported by grants from the National Science Council (Grants NSC 90-2320-B-002-135, NSC 90-2320-B-002-159, NSC 91-2320-B-002-100 and NSC91-2320-B-002-178) and National Health Research Institutes, Taiwan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jen-Yang Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, MT., Chen, YR., Chen, SC. et al. Epstein–Barr virus latent membrane protein 1 induces micronucleus formation, represses DNA repair and enhances sensitivity to DNA-damaging agents in human epithelial cells. Oncogene 23, 2531–2539 (2004). https://doi.org/10.1038/sj.onc.1207375

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207375

Keywords

This article is cited by

Search

Quick links