{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:50:46Z","timestamp":1791496246205,"version":"4.3.4"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2002,1,1]],"date-time":"2002-01-01T00:00:00Z","timestamp":1009843200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2003,12,30]],"date-time":"2003-12-30T00:00:00Z","timestamp":1072742400000},"content-version":"vor","delay-in-days":728,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"M.D."},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["Pe\/608 2-3"],"award-info":[{"award-number":["Pe\/608 2-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"C.E.R."},{"name":"Irma T. Hirschl-Weiler"},{"name":"H.W."},{"name":"Bundesministerium f\u00fcr Gesundheit and the Hansestadt Hamburg"},{"name":"J.P."}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Chronic infection with hepatitis B virus (HBV) is associated with an increased risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Although clonal HBV DNA integrations are detected in nearly all HCCs the role of these integrations in hepatocarcinogenesis is poorly understood. We have used a cloning protocol that allows studying the frequency and the natural history of HBV DNA integrations in cell culture. Southern blot analysis of the genomic DNA of HepG2 2.2.15 subclones, which replicate HBV, enabled us to detect new HBV DNA integrations in approximately 10% of the HepG 2.2.15 subclones over 4 rounds of sequential subcloning, whereas no loss of any preexisting HBV DNA integrations was observed. Treatments of HepG2 cells with H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      , designed to increase DNA damage, increased the frequency of HBV integrations to approximately 50% of the subclones and treatments designed to inhibit DNA repair, by inhibiting Poly(ADP-ribosyl)ation, also increased the frequency of HBV integration to 50%. These findings suggest that DNA strand breaks induced by oxidative stress during persistent HBV infection in humans may increase HBV DNA integration events, whereas PARP-1 activity may function to limit the occurrence of\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      HBV DNA integrations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1053\/jhep.2002.30203","type":"journal-article","created":{"date-parts":[[2002,8,24]],"date-time":"2002-08-24T23:46:10Z","timestamp":1030232770000},"page":"217-223","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":90,"title":["Increase in de novo HBV DNA integrations in response to oxidative DNA damage or inhibition of poly(ADP-ribosyl)ation"],"prefix":"10.1097","volume":"35","author":[{"given":"Maura","family":"Dandri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Burda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"B\u00fcrkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Zuckerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Will","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Rogler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heimer","family":"Greten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2002.30203-BIB1|cit1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0753-3322(97)86239-7","article-title":"Hepatitis B viruses and cancerogenesis","volume":"52","author":"Buendia","year":"1998","journal-title":"Biomed Pharmacother"},{"key":"10.1053\/jhep.2002.30203-BIB2|cit2","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1056\/NEJM199903113401001","article-title":"Rising incidence of hepatocellular carcinoma in the United States","volume":"340","author":"El-Serag","year":"1999","journal-title":"N Engl J Med"},{"key":"10.1053\/jhep.2002.30203-BIB3|cit3","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1002\/1097-0142(19880515)61:10<1942::AID-CNCR2820611003>3.0.CO;2-J","article-title":"Hepatitis B virus-the major etiology of hepatocellular carcinoma","volume":"61","author":"Beasley","year":"1988","journal-title":"Cancer"},{"key":"10.1053\/jhep.2002.30203-BIB4|cit4","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/S0140-6736(81)90585-7","article-title":"Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan","volume":"2","author":"Beasley","year":"1981","journal-title":"Lancet"},{"key":"10.1053\/jhep.2002.30203-BIB5|cit5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.iy.13.040195.000333","article-title":"Hepatitis B virus immunopathogenesis","volume":"13","author":"Chisari","year":"1995","journal-title":"Annu Rev Immunol"},{"key":"10.1053\/jhep.2002.30203-BIB6|cit6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/351317a0","article-title":"HBx gene of hepatitis B virus induces liver cancer in transgenic mice","volume":"351","author":"Kim","year":"1991","journal-title":"Nature"},{"key":"10.1053\/jhep.2002.30203-BIB7|cit7","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.1128\/JVI.70.8.5246-5254.1996","article-title":"Woodchuck hepatitis virus X protein is present in chronically infected woodchuck liver and woodchuck hepatocellular carcinomas which are permissive for viral replication","volume":"70","author":"Dandri","year":"1996","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB8|cit8","doi-asserted-by":"crossref","first-page":"9359","DOI":"10.1128\/JVI.72.11.9359-9364.1998","article-title":"Metabolic labeling of woodchuck hepatitis B virus X protein in naturally infected hepatocytes reveals a bimodal half-life and association with the nuclear framework","volume":"72","author":"Dandri","year":"1998","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB9|cit9","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/0092-8674(89)90770-8","article-title":"Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice","volume":"59","author":"Chisari","year":"1989","journal-title":"Cell"},{"key":"10.1053\/jhep.2002.30203-BIB10|cit10","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/343457a0","article-title":"The preS2\/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator","volume":"343","author":"Kekule","year":"1990","journal-title":"Nature"},{"key":"10.1053\/jhep.2002.30203-BIB11|cit11","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/347294a0","article-title":"Frequent activation of N-myc genes by hepadnaviral insertion in woodchuck liver tumors","volume":"347","author":"Fourel","year":"1990","journal-title":"Nature"},{"key":"10.1053\/jhep.2002.30203-BIB12|cit12","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1002\/j.1460-2075.1994.tb06542.x","article-title":"Evidence for long-range oncogene activation by hepadnavirus insertion","volume":"13","author":"Fourel","year":"1994","journal-title":"EMBO J"},{"key":"10.1053\/jhep.2002.30203-BIB13|cit13","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1101\/gad.1.8.773","article-title":"The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma","volume":"1","author":"Nagaya","year":"1987","journal-title":"Genes Dev"},{"key":"10.1053\/jhep.2002.30203-BIB14|cit14","first-page":"103","article-title":"Cellular and molecular mechanisms of hepatocarcinogenesis associated with hepadnavirus infection","volume":"168","author":"Rogler","year":"1991","journal-title":"Curr Top Microbiol Immunol"},{"key":"10.1053\/jhep.2002.30203-BIB15|cit15","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/286533a0","article-title":"Presence of integrated hepatitis B virus DNA sequences in cellular DNA in human hepatocellular carcinoma","volume":"286","author":"Brechot","year":"1980","journal-title":"Nature"},{"key":"10.1053\/jhep.2002.30203-BIB16|cit16","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1056\/NEJM198110293051807","article-title":"Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma","volume":"305","author":"Shafritz","year":"1981","journal-title":"N Engl J Med"},{"key":"10.1053\/jhep.2002.30203-BIB17|cit17","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/(SICI)1098-2264(199701)18:1<59::AID-GCC7>3.0.CO;2-0","article-title":"Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization","volume":"18","author":"Marchio","year":"1997","journal-title":"Gen Chromosomes Cancer"},{"key":"10.1053\/jhep.2002.30203-BIB18|cit18","first-page":"1986","article-title":"Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by high-resolution allelotype","volume":"57","author":"Boige","year":"1997","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2002.30203-BIB19|cit19","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1128\/JVI.70.3.2000-2007.1996","article-title":"Loss and acquisition of duck hepatitis B virus integrations in lineages of LMH-D2 chicken hepatoma cells","volume":"70","author":"Gong","year":"1996","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB20|cit20","doi-asserted-by":"crossref","first-page":"9710","DOI":"10.1128\/JVI.73.12.9710-9717.1999","article-title":"Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor","volume":"73","author":"Yang","year":"1999","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB21|cit21","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1093\/nar\/27.8.1919","article-title":"Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro","volume":"27","author":"Pourquier","year":"1999","journal-title":"Nucleic Acids Res"},{"key":"10.1053\/jhep.2002.30203-BIB22|cit22","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1126\/science.2996131","article-title":"Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma","volume":"230","author":"Rogler","year":"1985","journal-title":"Science"},{"key":"10.1053\/jhep.2002.30203-BIB23|cit23","doi-asserted-by":"crossref","first-page":"12808","DOI":"10.1073\/pnas.91.26.12808","article-title":"Extensive oxidative damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma","volume":"91","author":"Hagen","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2002.30203-BIB24|cit24","first-page":"3171","article-title":"Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis","volume":"54","author":"Shimoda","year":"1994","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2002.30203-BIB25|cit25","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/bies.1115","article-title":"Physiology and pathophysiology of poly(ADP-ribosyl)ation","volume":"23","author":"B\u00fcrkle","year":"2001","journal-title":"BioEssays"},{"key":"10.1053\/jhep.2002.30203-BIB26|cit26","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1093\/nar\/26.11.2644","article-title":"DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines","volume":"26","author":"Trucco","year":"1998","journal-title":"Nucleic Acids Res"},{"key":"10.1053\/jhep.2002.30203-BIB27|cit27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/BF00928441","article-title":"Interaction of poly(ADP-ribose)polymerase with DNA polymerase alpha","volume":"138","author":"Yoshida","year":"1994","journal-title":"Mol Cell Biochem"},{"key":"10.1053\/jhep.2002.30203-BIB28|cit28","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/1097-0215(20001101)88:3<351::AID-IJC5>3.0.CO;2-H","article-title":"Negative regulation of alkylation-induced sister-chromatid exchanges by poly(ADP-ribose)polymerase-1 activity","volume":"88","author":"Meyer","year":"2000","journal-title":"Int J Cancer"},{"key":"10.1053\/jhep.2002.30203-BIB29|cit29","first-page":"2703","volume-title":"Virology","volume":"2","author":"Ganem","year":"1996"},{"key":"10.1053\/jhep.2002.30203-BIB30|cit30","doi-asserted-by":"crossref","first-page":"5455","DOI":"10.1128\/JVI.71.7.5455-5463.1997","article-title":"Increase in the frequency of hepadnavirus DNA integrations by oxidative DNA damage and inhibition of DNA repair","volume":"71","author":"Petersen","year":"1997","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB31|cit31","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1128\/JVI.73.2.1492-1502.1999","article-title":"Double-stranded linear duck hepatitis B virus (DHBV) stably integrates at a higher frequency than wild-type DHBV in LMH chicken hepatoma cells","volume":"73","author":"Gong","year":"1999","journal-title":"J Virol"},{"key":"10.1053\/jhep.2002.30203-BIB32|cit32","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1073\/pnas.84.4.1005","article-title":"Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA","volume":"84","author":"Sells","year":"1987","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2002.30203-BIB33|cit33","first-page":"379","article-title":"Expression of hepatitis B virus DNA sequences in cell culture","volume":"9","author":"Acs","year":"1990","journal-title":"Prog Liver Dis"},{"key":"10.1053\/jhep.2002.30203-BIB34|cit34","doi-asserted-by":"crossref","first-page":"4908","DOI":"10.1073\/pnas.83.13.4908","article-title":"Hydrogen peroxide-induced injury of cells and its prevention by poly(ADP-ribose) polymerase","volume":"83","author":"Schraufstatter","year":"1986","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2002.30203-BIB35|cit35","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1172\/JCI112436","article-title":"Oxidant injury of cells","volume":"77","author":"Schraufstatter","year":"1986","journal-title":"J Clin Invest"},{"key":"10.1053\/jhep.2002.30203-BIB36|cit36","first-page":"620","article-title":"Strong, sustained hepatocellular proliferation proceeds hepatocarcinogenesis in hepatitis B surface antigen positive transgenic mice","volume":"21","author":"Huang","year":"1995","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.30203-BIB37|cit37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/bbrc.1998.8257","article-title":"Cellular responses to DNA damage in the absence of Poly(ADP-ribose) polymerase","volume":"245","author":"Le Rhun","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1053\/jhep.2002.30203-BIB38|cit38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF00928445","article-title":"The function of poly(ADP-ribosylation) in DNA breakage and rejoining","volume":"138","author":"Shall","year":"1994","journal-title":"Mol Cell Biochem"},{"key":"10.1053\/jhep.2002.30203-BIB39|cit39","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1126\/science.286.5446.1897","article-title":"Quality control by DNA repair","volume":"286","author":"Lindahl","year":"1999","journal-title":"Science"},{"key":"10.1053\/jhep.2002.30203-BIB40|cit40","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/jmv.1890420406","article-title":"Tumor suppressor genes, growth factor genes, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma","volume":"42","author":"Tabor","year":"1994","journal-title":"J Med Virol"},{"key":"10.1053\/jhep.2002.30203-BIB41|cit41","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/hep.1840220403","article-title":"Characteristic difference of hepatocellular carcinoma between hepatitis B- and C-viral infection","volume":"22","author":"Shiratoi","year":"1995","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.30203-BIB42|cit42","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1002\/1097-0142(19891201)64:11<2377::AID-CNCR2820641130>3.0.CO;2-8","article-title":"Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma","volume":"64","author":"Chang","year":"1989","journal-title":"Cancer"},{"key":"10.1053\/jhep.2002.30203-BIB43|cit43","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1002\/hep.1840130218","article-title":"Hepatitis B Virus Integration in Hepatitis B virus-related hepatocellular carcinoma","volume":"13","author":"Chang","year":"1991","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.30203-BIB44|cit44","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1097\/00005176-199301000-00013","article-title":"Patterns of hepatitis B virus DNA integration in liver tissue of children with chronic infections","volume":"16","author":"Goto","year":"1993","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"10.1053\/jhep.2002.30203-BIB45|cit45","first-page":"243","article-title":"Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis","volume":"7","author":"Matsubara","year":"1990","journal-title":"Mol Biol Med"},{"key":"10.1053\/jhep.2002.30203-BIB46|cit46","first-page":"6810","article-title":"Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules","volume":"52","author":"Yasui","year":"1992","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2002.30203-BIB47|cit47","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/S0016-5085(88)80093-3","article-title":"Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma","volume":"95","author":"Tsuda","year":"1988","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.30203-BIB48|cit48","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1002\/hep.510290523","article-title":"Hino O Determination of the clonal origin of multiple human hepatocellular carcinomas by cloning and polymerase chain reaction of the integrated hepatitis B virus DNA","volume":"29","author":"Yamamoto","year":"1999","journal-title":"Hepatology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1053%2Fjhep.2002.30203","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1053%2Fjhep.2002.30203","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200201000-00029","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T10:57:25Z","timestamp":1738925845000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200201000-00029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,1]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2002]]}},"URL":"https:\/\/doi.org\/10.1053\/jhep.2002.30203","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2002,1]]}}}