{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:09:36Z","timestamp":1790806176288,"version":"4.1.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"New Jersey Commission on Cancer Research"},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI138797"],"award-info":[{"award-number":["R01 AI138797"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-15-048-01-MPC"],"award-info":[{"award-number":["RSG-15-048-01-MPC"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Microbiol"],"DOI":"10.1038\/s41564-020-0678-0","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T17:03:07Z","timestamp":1583773387000},"page":"715-726","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation"],"prefix":"10.1038","volume":"5","author":[{"given":"Lei","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9322-7252","authenticated-orcid":false,"given":"Alexander","family":"Ploss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,9]]},"reference":[{"key":"678_CR1","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.coviro.2015.06.004","volume":"13","author":"BY Winer","year":"2015","unstructured":"Winer, B. Y. & Ploss, A. Determinants of hepatitis B and delta virus host tropism. Curr. Opin. Virol. 13, 109\u2013116 (2015).","journal-title":"Curr. Opin. Virol."},{"key":"678_CR2","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1136\/gutjnl-2015-309809","volume":"64","author":"M Nassal","year":"2015","unstructured":"Nassal, M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64, 1972\u20131984 (2015).","journal-title":"Gut"},{"key":"678_CR3","doi-asserted-by":"publisher","first-page":"e00049","DOI":"10.7554\/eLife.00049","volume":"1","author":"H Yan","year":"2012","unstructured":"Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049 (2012).","journal-title":"eLife"},{"key":"678_CR4","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/0092-8674(92)90599-8","volume":"71","author":"GH Wang","year":"1992","unstructured":"Wang, G. H. & Seeger, C. The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell 71, 663\u2013670 (1992).","journal-title":"Cell"},{"key":"678_CR5","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/0092-8674(80)90443-2","volume":"21","author":"WH Gerlich","year":"1980","unstructured":"Gerlich, W. H. & Robinson, W. S. Hepatitis B virus contains protein attached to the 5\u02b9 terminus of its complete DNA strand. Cell 21, 801\u2013809 (1980).","journal-title":"Cell"},{"key":"678_CR6","doi-asserted-by":"publisher","first-page":"S41","DOI":"10.1016\/j.jhep.2016.02.009","volume":"64","author":"J Lucifora","year":"2016","unstructured":"Lucifora, J. & Protzer, U. Attacking hepatitis B virus cccDNA\u2014the holy grail to hepatitis B cure. J. Hepatol. 64, S41\u2013S48 (2016).","journal-title":"J. Hepatol."},{"key":"678_CR7","doi-asserted-by":"publisher","first-page":"E4244","DOI":"10.1073\/pnas.1409986111","volume":"111","author":"C Koniger","year":"2014","unstructured":"Koniger, C. et al. Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proc. Natl Acad. Sci. USA 111, E4244\u2013E4253 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"678_CR8","doi-asserted-by":"publisher","first-page":"6164","DOI":"10.1128\/JVI.02721-06","volume":"81","author":"W Gao","year":"2007","unstructured":"Gao, W. & Hu, J. Formation of hepatitis B virus covalently closed circular DNA: removal of genome-linked protein. J. Virol. 81, 6164\u20136174 (2007).","journal-title":"J. Virol."},{"key":"678_CR9","doi-asserted-by":"publisher","first-page":"12472","DOI":"10.1128\/JVI.01123-07","volume":"81","author":"H Guo","year":"2007","unstructured":"Guo, H. et al. Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: an intermediate of covalently closed circular DNA formation. J. Virol. 81, 12472\u201312484 (2007).","journal-title":"J. Virol."},{"key":"678_CR10","doi-asserted-by":"publisher","first-page":"a021386","DOI":"10.1101\/cshperspect.a021386","volume":"5","author":"J Hu","year":"2015","unstructured":"Hu, J. & Seeger, C. Hepadnavirus genome replication and persistence. Cold Spring Harb. Perspect. Med. 5, a021386 (2015).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"678_CR11","doi-asserted-by":"publisher","first-page":"e1005893","DOI":"10.1371\/journal.ppat.1005893","volume":"12","author":"Y Qi","year":"2016","unstructured":"Qi, Y. et al. DNA polymerase \u03ba is a key cellular factor for the formation of covalently closed circular DNA of hepatitis B virus. PLoS Pathog. 12, e1005893 (2016).","journal-title":"PLoS Pathog."},{"key":"678_CR12","doi-asserted-by":"publisher","first-page":"e1006784","DOI":"10.1371\/journal.ppat.1006784","volume":"13","author":"Q Long","year":"2017","unstructured":"Long, Q. et al. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLoS Pathog. 13, e1006784 (2017).","journal-title":"PLoS Pathog."},{"key":"678_CR13","doi-asserted-by":"publisher","first-page":"e0128401","DOI":"10.1371\/journal.pone.0128401","volume":"10","author":"X Cui","year":"2015","unstructured":"Cui, X. et al. Does tyrosyl DNA phosphodiesterase-2 play a role in hepatitis B virus genome repair? PLoS ONE 10, e0128401 (2015).","journal-title":"PLoS ONE"},{"key":"678_CR14","doi-asserted-by":"publisher","first-page":"e1007124","DOI":"10.1371\/journal.ppat.1007124","volume":"14","author":"K Kitamura","year":"2018","unstructured":"Kitamura, K. et al. Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus. PLoS Pathog. 14, e1007124 (2018).","journal-title":"PLoS Pathog."},{"key":"678_CR15","doi-asserted-by":"publisher","first-page":"e1007742","DOI":"10.1371\/journal.ppat.1007742","volume":"15","author":"L Tang","year":"2019","unstructured":"Tang, L., Sheraz, M., McGrane, M., Chang, J. & Guo, J. T. DNA polymerase alpha is essential for intracellular amplification of hepatitis B virus covalently closed circular DNA. PLoS Pathog. 15, e1007742 (2019).","journal-title":"PLoS Pathog."},{"key":"678_CR16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.3390\/v9060139","volume":"9","author":"X Li","year":"2017","unstructured":"Li, X., Zhao, J., Yuan, Q. & Xia, N. Detection of HBV covalently closed circular DNA. Viruses 9, 139 (2017).","journal-title":"Viruses"},{"key":"678_CR17","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1128\/JVI.45.1.165-172.1983","volume":"45","author":"KL Molnar-Kimber","year":"1983","unstructured":"Molnar-Kimber, K. L., Summers, J., Taylor, J. M. & Mason, W. S. Protein covalently bound to minus-strand DNA intermediates of duck hepatitis B virus. J. Virol. 45, 165\u2013172 (1983).","journal-title":"J. Virol."},{"key":"678_CR18","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/j.jhep.2017.02.004","volume":"66","author":"Z Yan","year":"2017","unstructured":"Yan, Z. et al. HBVcircle: a novel tool to investigate hepatitis B virus covalently closed circular DNA. J. Hepatol. 66, 1149\u20131157 (2017).","journal-title":"J. Hepatol."},{"key":"678_CR19","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1146\/annurev.biochem.67.1.721","volume":"67","author":"S Waga","year":"1998","unstructured":"Waga, S. & Stillman, B. The DNA replication fork in eukaryotic cells. Annu. Rev. Biochem. 67, 721\u2013751 (1998).","journal-title":"Annu. Rev. Biochem."},{"key":"678_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00200-8","volume":"8","author":"BY Winer","year":"2017","unstructured":"Winer, B. Y. et al. Long-term hepatitis B infection in a scalable hepatic co-culture system. Nat. Commun. 8, 125 (2017).","journal-title":"Nat. Commun."},{"key":"678_CR21","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/0014-5793(94)80254-8","volume":"341","author":"GE Wright","year":"1994","unstructured":"Wright, G. E., Hubscher, U., Khan, N. N., Focher, F. & Verri, A. Inhibitor analysis of calf thymus DNA polymerases \u03b1, \u03b4 and \u03f5. FEBS Lett. 341, 128\u2013130 (1994).","journal-title":"FEBS Lett"},{"key":"678_CR22","doi-asserted-by":"publisher","first-page":"e01117-18","DOI":"10.1128\/JVI.01117-18","volume":"92","author":"B Qu","year":"2018","unstructured":"Qu, B., Ni, Y., Lempp, F. A., Vondran, F. W. R. & Urban, S. T5 exonuclease hydrolysis of hepatitis B virus replicative intermediates allows reliable quantification and fast drug efficacy testing of covalently closed circular DNA by PCR. J. Virol. 92, e01117-18 (2018).","journal-title":"J. Virol."},{"key":"678_CR23","doi-asserted-by":"publisher","first-page":"e00539-17","DOI":"10.1128\/JVI.00539-17","volume":"91","author":"J Luo","year":"2017","unstructured":"Luo, J., Cui, X., Gao, L. & Hu, J. Identification of intermediate in hepatitis B virus CCC DNA formation and sensitive and selective CCC DNA detection. J. Virol. 91, e00539-17 (2017).","journal-title":"J. Virol."},{"key":"678_CR24","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/978-1-62703-484-5_13","volume":"1030","author":"D Cai","year":"2013","unstructured":"Cai, D. et al. A Southern blot assay for detection of hepatitis B virus covalently closed circular DNA from cell cultures. Methods Mol. Biol. 1030, 151\u2013161 (2013).","journal-title":"Methods Mol. Biol."},{"key":"678_CR25","doi-asserted-by":"publisher","first-page":"5204","DOI":"10.1038\/sj.onc.1205561","volume":"21","author":"E Parlanti","year":"2002","unstructured":"Parlanti, E., Fortini, P., Macpherson, P., Laval, J. & Dogliotti, E. Base excision repair of adenine\/8-oxoguanine mispairs by an aphidicolin-sensitive DNA polymerase in human cell extracts. Oncogene 21, 5204\u20135212 (2002).","journal-title":"Oncogene"},{"key":"678_CR26","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1016\/S0021-9258(19)67858-0","volume":"266","author":"DC Thomas","year":"1991","unstructured":"Thomas, D. C., Roberts, J. D. & Kunkel, T. A. Heteroduplex repair in extracts of human HeLa cells. J. Biol. Chem. 266, 3744\u20133751 (1991).","journal-title":"J. Biol. Chem."},{"key":"678_CR27","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/S1097-2765(00)80277-4","volume":"2","author":"X Zhao","year":"1998","unstructured":"Zhao, X., Muller, E. G. & Rothstein, R. A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Mol. Cell 2, 329\u2013340 (1998).","journal-title":"Mol. Cell"},{"key":"678_CR28","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1073\/pnas.84.4.1005","volume":"84","author":"MA Sells","year":"1987","unstructured":"Sells, M. A., Chen, M. L. & Acs, G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc. Natl Acad. Sci. USA 84, 1005\u20131009 (1987).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"678_CR29","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1038\/nbt.1708","volume":"28","author":"MA Kay","year":"2010","unstructured":"Kay, M. A., He, C. Y. & Chen, Z. Y. A robust system for production of minicircle DNA vectors. Nat. Biotechnol. 28, 1287\u20131289 (2010).","journal-title":"Nat. Biotechnol."},{"key":"678_CR30","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1038\/msb4100050","volume":"2","author":"T Baba","year":"2006","unstructured":"Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006 (2006).","journal-title":"Mol. Syst. Biol."},{"key":"678_CR31","first-page":"e4140","volume":"64","author":"EG Folco","year":"2012","unstructured":"Folco, E. G., Lei, H., Hsu, J. L. & Reed, R. Small-scale nuclear extracts for functional assays of gene-expression machineries. J. Vis. Exp. 64, e4140 (2012).","journal-title":"J. Vis. Exp."},{"key":"678_CR32","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-1-4939-6700-1_2","volume":"1540","author":"Y Ni","year":"2017","unstructured":"Ni, Y., Urban, S. & Hepatitis, B. Virus infection of HepaRG cells, HepaRG-hNTCP cells, and primary human hepatocytes. Methods Mol. Biol. 1540, 15\u201325 (2017).","journal-title":"Methods Mol. Biol."},{"key":"678_CR33","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1128\/JVI.12.5.995-1005.1973","volume":"12","author":"PM Kaplan","year":"1973","unstructured":"Kaplan, P. M., Greenman, R. L., Gerin, J. L., Purcell, R. H. & Robinson, W. S. DNA polymerase associated with human hepatitis B antigen. J. Virol. 12, 995\u20131005 (1973).","journal-title":"J. Virol."},{"key":"678_CR34","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/nmeth.3776","volume":"13","author":"OR Collaboration","year":"2016","unstructured":"Collaboration, O. R. The ORFeome Collaboration: a genome-scale human ORF-clone resource. Nat. Methods 13, 191\u2013192 (2016).","journal-title":"Nat. Methods"},{"key":"678_CR35","doi-asserted-by":"publisher","first-page":"8495","DOI":"10.1073\/pnas.0903654106","volume":"106","author":"FA Kadyrov","year":"2009","unstructured":"Kadyrov, F. A. et al. A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair. Proc. Natl Acad. Sci. USA 106, 8495\u20138500 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Nature Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41564-020-0678-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-020-0678-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-020-0678-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T04:19:37Z","timestamp":1670300377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41564-020-0678-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,9]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["678"],"URL":"https:\/\/doi.org\/10.1038\/s41564-020-0678-0","relation":{},"ISSN":["2058-5276"],"issn-type":[{"value":"2058-5276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,9]]},"assertion":[{"value":"29 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}