{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:26:33Z","timestamp":1790047593973,"version":"4.0.1"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1949,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,5]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Hepatitis B virus (HBV) causes liver diseases from acute hepatitis to cirrhosis and liver cancer. Currently, more than 350 million people are chronic HBV carriers, with devastating prognosis. HBV is a small enveloped noncytopathic virus, containing a circular partially double-stranded DNA genome, and exhibits strong tropism for human liver cells. Infected individuals (acute and chronic) secrete about 107 to 1011 virions per day to the bloodstream, with each infected cell releasing 50-300 viruses per day. HBV infects nondividing hepatocytes and replicates by reverse-transcribing the pregenomic RNA to DNA in the host cells. The level of deoxyribonucleotide triphosphates (dNTPs) in nondividing cells is too low to support viral replication and enable the high yield of secreted virions. Here, we report production of dNTPs by viral-dependent transcription activation of R2, the key component of ribonucleotide reductase (RNR), and show that this process is critical for the HBV life-cycle. This was found in an established HBV-positive cell line and was reproduced by HBV DNA\u2013transduced cells, in both culture and mice. Furthermore, the viral hepatitis B X protein is essential in activating R2 expression by blocking access of Regulatory factor x1, a repressor of the R2 gene.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Our findings demonstrate that the hepatitis B X protein is critical in infecting nonproliferating hepatocytes, which contain a low dNTP level. In addition, we provide molecular evidence for a new mechanism of HBV\u2013host cell interaction where RNR-R2, a critical cell-cycle gene, is selectively activated in nonproliferating cells. This mechanism may set the stage for formulating a new category of anti-HBV drugs. (Hepatology 2010)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.23519","type":"journal-article","created":{"date-parts":[[2009,12,23]],"date-time":"2009-12-23T14:18:37Z","timestamp":1261577917000},"page":"1538-1546","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":41,"title":["Hepatitis B Virus Activates Deoxynucleotide Synthesis in Nondividing Hepatocytes by Targeting the R2 Gene"],"prefix":"10.1097","volume":"51","author":[{"given":"Dorit","family":"Cohen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaarit","family":"Adamovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Reuven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosef","family":"Shaul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-11-20250312","doi-asserted-by":"crossref","first-page":"11181129","DOI":"10.1056\/NEJMra031087","article-title":"Hepatitis B virus infectionnatural history and clinical consequences.","volume":"350","author":"Ganem","year":"2004","journal-title":"N Engl J Med"},{"key":"R2-11-20250312","doi-asserted-by":"crossref","first-page":"651693","DOI":"10.1146\/annurev.bi.56.070187.003251","article-title":"The molecular biology of the hepatitis B viruses.","volume":"56","author":"Ganem","year":"1987","journal-title":"Annu Rev Biochem"},{"key":"R3-11-20250312","first-page":"543547","article-title":"Effects of cell cycle on telomerase activity and on hepatitis B virus replication in HepG2 2.2.15 cells.","volume":"3","author":"Huang","year":"2004","journal-title":"Hepatobiliary Pancreat Dis Int"},{"key":"R4-11-20250312","first-page":"349354","article-title":"Deoxyribonucleoside triphosphate pools in regenerating rat liver: effect of hydroxyurea and exogenous deoxypyrimidines.","volume":"992","author":"Rottgen","year":"1989","journal-title":"Biochim Biophys Acta"},{"key":"R5-11-20250312","doi-asserted-by":"crossref","first-page":"10051013","DOI":"10.1128\/AAC.46.4.1005-1013.2002","article-title":"Kinetic analysis of wildtype and YMDD mutant hepatitis B virus polymerases and effects of deoxyribonucleotide concentrations on polymerase 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