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. 1995 Feb;69(2):1107–1114. doi: 10.1128/jvi.69.2.1107-1114.1995

Hepatitis B virus X protein interacts with a probable cellular DNA repair protein.

T H Lee 1, S J Elledge 1, J S Butel 1
PMCID: PMC188683  PMID: 7815490

Abstract

The mechanism of action of hepatitis B virus (HBV) X protein in transcriptional transactivation and in tumorigenesis remains obscure. We have used the yeast two-hybrid system to identify a cellular protein that can interact with HBV X protein. This protein, designated X-associated protein 1 (XAP-1), is a human homolog of the UV-damaged DNA-binding protein (UV-DDB) recovered from a monkey cell cDNA library. UV-DDB is presumed to be involved in DNA repair. The interaction between X protein and XAP-1 protein was verified by immunoprecipitation of yeast cell lysates expressing both proteins and by in vitro mixing with X protein expressed as a glutathione S-transferase fusion protein and XAP-1 protein either in HeLa cell extracts or synthesized by in vitro translation. We speculate that the interaction of X protein with a DNA repair protein may recruit cellular proteins to repair the partially double-stranded HBV genome or may modify cellular transcription processes. An effect on the cellular DNA repair system may explain a cofactor role for HBV in liver cancer development.

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Selected References

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  1. Arii M., Takada S., Koike K. Identification of three essential regions of hepatitis B virus X protein for trans-activation function. Oncogene. 1992 Mar;7(3):397–403. [PubMed] [Google Scholar]
  2. Blum H. E., Zhang Z. S., Galun E., von Weizsäcker F., Garner B., Liang T. J., Wands J. R. Hepatitis B virus X protein is not central to the viral life cycle in vitro. J Virol. 1992 Feb;66(2):1223–1227. doi: 10.1128/jvi.66.2.1223-1227.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bootsma D., Hoeijmakers J. H. DNA repair. Engagement with transcription. Nature. 1993 May 13;363(6425):114–115. doi: 10.1038/363114a0. [DOI] [PubMed] [Google Scholar]
  4. Breeden L., Nasmyth K. Regulation of the yeast HO gene. Cold Spring Harb Symp Quant Biol. 1985;50:643–650. doi: 10.1101/sqb.1985.050.01.078. [DOI] [PubMed] [Google Scholar]
  5. Bronner C. E., Baker S. M., Morrison P. T., Warren G., Smith L. G., Lescoe M. K., Kane M., Earabino C., Lipford J., Lindblom A. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17;368(6468):258–261. doi: 10.1038/368258a0. [DOI] [PubMed] [Google Scholar]
  6. Buendia M. A. Hepatitis B viruses and hepatocellular carcinoma. Adv Cancer Res. 1992;59:167–226. doi: 10.1016/s0065-230x(08)60306-1. [DOI] [PubMed] [Google Scholar]
  7. Chen H. S., Kaneko S., Girones R., Anderson R. W., Hornbuckle W. E., Tennant B. C., Cote P. J., Gerin J. L., Purcell R. H., Miller R. H. The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol. 1993 Mar;67(3):1218–1226. doi: 10.1128/jvi.67.3.1218-1226.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cross J. C., Wen P., Rutter W. J. Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8078–8082. doi: 10.1073/pnas.90.17.8078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Donehower L. A., Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. doi: 10.1016/0304-419x(93)90004-v. [DOI] [PubMed] [Google Scholar]
  10. Durfee T., Becherer K., Chen P. L., Yeh S. H., Yang Y., Kilburn A. E., Lee W. H., Elledge S. J. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 1993 Apr;7(4):555–569. doi: 10.1101/gad.7.4.555. [DOI] [PubMed] [Google Scholar]
  11. Feitelson M. A., Zhu M., Duan L. X., London W. T. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene. 1993 May;8(5):1109–1117. [PubMed] [Google Scholar]
  12. Fields S., Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. doi: 10.1038/340245a0. [DOI] [PubMed] [Google Scholar]
  13. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  14. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  15. Hwang B. J., Chu G. Purification and characterization of a human protein that binds to damaged DNA. Biochemistry. 1993 Feb 16;32(6):1657–1666. doi: 10.1021/bi00057a033. [DOI] [PubMed] [Google Scholar]
  16. Jarvis D. L., Butel J. S. Modification of simian virus 40 large tumor antigen by glycosylation. Virology. 1985 Mar;141(2):173–189. doi: 10.1016/0042-6822(85)90250-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jerry D. J., Ozbun M. A., Kittrell F. S., Lane D. P., Medina D., Butel J. S. Mutations in p53 are frequent in the preneoplastic stage of mouse mammary tumor development. Cancer Res. 1993 Jul 15;53(14):3374–3381. [PubMed] [Google Scholar]
  18. Kaelin W. G., Jr, Krek W., Sellers W. R., DeCaprio J. A., Ajchenbaum F., Fuchs C. S., Chittenden T., Li Y., Farnham P. J., Blanar M. A. Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992 Jul 24;70(2):351–364. doi: 10.1016/0092-8674(92)90108-o. [DOI] [PubMed] [Google Scholar]
  19. Keeney S., Eker A. P., Brody T., Vermeulen W., Bootsma D., Hoeijmakers J. H., Linn S. Correction of the DNA repair defect in xeroderma pigmentosum group E by injection of a DNA damage-binding protein. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4053–4056. doi: 10.1073/pnas.91.9.4053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kekulé A. S., Lauer U., Weiss L., Luber B., Hofschneider P. H. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature. 1993 Feb 25;361(6414):742–745. doi: 10.1038/361742a0. [DOI] [PubMed] [Google Scholar]
  21. Kim C. M., Koike K., Saito I., Miyamura T., Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991 May 23;351(6324):317–320. doi: 10.1038/351317a0. [DOI] [PubMed] [Google Scholar]
  22. Köck J., Schlicht H. J. Analysis of the earliest steps of hepadnavirus replication: genome repair after infectious entry into hepatocytes does not depend on viral polymerase activity. J Virol. 1993 Aug;67(8):4867–4874. doi: 10.1128/jvi.67.8.4867-4874.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lanford R. E., Butel J. S. Antigenic relationship of SV40 early proteins to purified large T polypeptide. Virology. 1979 Sep;97(2):295–306. doi: 10.1016/0042-6822(79)90341-6. [DOI] [PubMed] [Google Scholar]
  24. Leach F. S., Nicolaides N. C., Papadopoulos N., Liu B., Jen J., Parsons R., Peltomäki P., Sistonen P., Aaltonen L. A., Nyström-Lahti M. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993 Dec 17;75(6):1215–1225. doi: 10.1016/0092-8674(93)90330-s. [DOI] [PubMed] [Google Scholar]
  25. Lee T. H., Finegold M. J., Shen R. F., DeMayo J. L., Woo S. L., Butel J. S. Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice. J Virol. 1990 Dec;64(12):5939–5947. doi: 10.1128/jvi.64.12.5939-5947.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Levine A. J. The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses. Virology. 1990 Aug;177(2):419–426. doi: 10.1016/0042-6822(90)90505-l. [DOI] [PubMed] [Google Scholar]
  27. Levine A. J. The tumor suppressor genes. Annu Rev Biochem. 1993;62:623–651. doi: 10.1146/annurev.bi.62.070193.003203. [DOI] [PubMed] [Google Scholar]
  28. Maguire H. F., Hoeffler J. P., Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science. 1991 May 10;252(5007):842–844. doi: 10.1126/science.1827531. [DOI] [PubMed] [Google Scholar]
  29. Münger K., Scheffner M., Huibregtse J. M., Howley P. M. Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv. 1992;12:197–217. [PubMed] [Google Scholar]
  30. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  31. Rossner M. T. Review: hepatitis B virus X-gene product: a promiscuous transcriptional activator. J Med Virol. 1992 Feb;36(2):101–117. doi: 10.1002/jmv.1890360207. [DOI] [PubMed] [Google Scholar]
  32. Runkel L., Fischer M., Schaller H. Two-codon insertion mutations of the HBx define two separate regions necessary for its trans-activation function. Virology. 1993 Dec;197(2):529–536. doi: 10.1006/viro.1993.1626. [DOI] [PubMed] [Google Scholar]
  33. Schaeffer L., Roy R., Humbert S., Moncollin V., Vermeulen W., Hoeijmakers J. H., Chambon P., Egly J. M. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science. 1993 Apr 2;260(5104):58–63. doi: 10.1126/science.8465201. [DOI] [PubMed] [Google Scholar]
  34. Slagle B. L., Lanford R. E., Medina D., Butel J. S. Expression of mammary tumor virus proteins in preneoplastic outgrowth lines and mammary tumors of BALB/cV mice. Cancer Res. 1984 May;44(5):2155–2162. [PubMed] [Google Scholar]
  35. Slagle B. L., Lee T. H., Butel J. S. Hepatitis B virus and hepatocellular carcinoma. Prog Med Virol. 1992;39:167–203. [PubMed] [Google Scholar]
  36. Takada S., Koike K. X protein of hepatitis B virus resembles a serine protease inhibitor. Jpn J Cancer Res. 1990 Dec;81(12):1191–1194. doi: 10.1111/j.1349-7006.1990.tb02675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Takao M., Abramic M., Moos M., Jr, Otrin V. R., Wootton J. C., McLenigan M., Levine A. S., Protic M. A 127 kDa component of a UV-damaged DNA-binding complex, which is defective in some xeroderma pigmentosum group E patients, is homologous to a slime mold protein. Nucleic Acids Res. 1993 Aug 25;21(17):4111–4118. doi: 10.1093/nar/21.17.4111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wang X. W., Forrester K., Yeh H., Feitelson M. A., Gu J. R., Harris C. C. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2230–2234. doi: 10.1073/pnas.91.6.2230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yaginuma K., Shirakata Y., Kobayashi M., Koike K. Hepatitis B virus (HBV) particles are produced in a cell culture system by transient expression of transfected HBV DNA. Proc Natl Acad Sci U S A. 1987 May;84(9):2678–2682. doi: 10.1073/pnas.84.9.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zoulim F., Saputelli J., Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol. 1994 Mar;68(3):2026–2030. doi: 10.1128/jvi.68.3.2026-2030.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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