{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T09:41:18Z","timestamp":1768729278347,"version":"3.49.0"},"reference-count":72,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T00:00:00Z","timestamp":1638662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["LTC20065"],"award-info":[{"award-number":["LTC20065"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ERDF\/ESF","award":["project ChemBioDrug CZ.02.1.01\/0.0\/0.0\/16_019\/0000729"],"award-info":[{"award-number":["project ChemBioDrug CZ.02.1.01\/0.0\/0.0\/16_019\/0000729"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Chronic hepatitis caused by infection with the Hepatitis B virus is a life-threatening condition. In fact, 1 million people die annually due to liver cirrhosis or hepatocellular carcinoma. Recently, several studies demonstrated a molecular connection between the host DNA damage response (DDR) pathway and HBV replication and reactivation. Here, we investigated the role of Ataxia-telangiectasia-mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) PI3-kinases in phosphorylation of the HBV core protein (HBc). We determined that treatment of HBc-expressing hepatocytes with genotoxic agents, e.g., etoposide or hydrogen peroxide, activated the host ATM-Chk2 pathway, as determined by increased phosphorylation of ATM at Ser1981 and Chk2 at Thr68. The activation of ATM led, in turn, to increased phosphorylation of cytoplasmic HBc at serine-glutamine (SQ) motifs located in its C-terminal domain. Conversely, down-regulation of ATM using ATM-specific siRNAs or inhibitor effectively reduced etoposide-induced HBc phosphorylation. Detailed mutation analysis of S-to-A HBc mutants revealed that S170 (S168 in a 183-aa HBc variant) is the primary site targeted by ATM-regulated phosphorylation. Interestingly, mutation of two major phosphorylation sites involving serines at positions 157 and 164 (S155 and S162 in a 183-aa HBc variant) resulted in decreased etoposide-induced phosphorylation, suggesting that the priming phosphorylation at these serine-proline (SP) sites is vital for efficient phosphorylation of SQ motifs. Notably, the mutation of S172 (S170 in a 183-aa HBc variant) had the opposite effect and resulted in massively up-regulated phosphorylation of HBc, particularly at S170. Etoposide treatment of HBV infected HepG2-NTCP cells led to increased levels of secreted HBe antigen and intracellular HBc protein. Together, our studies identified HBc as a substrate for ATM-mediated phosphorylation and mapped the phosphorylation sites. The increased expression of HBc and HBe antigens in response to genotoxic stress supports the idea that the ATM pathway may provide growth advantage to the replicating virus.<\/jats:p>","DOI":"10.3390\/v13122438","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T03:21:05Z","timestamp":1638847265000},"page":"2438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["ATM-Dependent Phosphorylation of Hepatitis B Core Protein in Response to Genotoxic Stress"],"prefix":"10.3390","volume":"13","author":[{"given":"Barbora","family":"Lubyova","sequence":"first","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Tikalova","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristyna","family":"Krulova","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hodek","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ales","family":"Zabransky","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1701-1438","authenticated-orcid":false,"given":"Ivan","family":"Hirsch","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"},{"name":"Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-7352","authenticated-orcid":false,"given":"Jan","family":"Weber","sequence":"additional","affiliation":[{"name":"IOCB Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1046\/j.1365-2893.2003.00487.x","article-title":"Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures","volume":"11","author":"Lavanchy","year":"2004","journal-title":"J. Viral Hepat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/nrclinonc.2012.1","article-title":"Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer","volume":"9","author":"Torres","year":"2012","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.jhep.2011.02.015","article-title":"Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection","volume":"55","author":"Lucifora","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev.mi.31.100177.002041","article-title":"The genome of hepatitis B virus","volume":"31","author":"Robinson","year":"1977","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.virol.2015.02.031","article-title":"Molecular biology of hepatitis B virus infection","volume":"479\u2013480","author":"Seeger","year":"2015","journal-title":"Virology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.antiviral.2017.11.015","article-title":"The diverse functions of the hepatitis B core\/capsid protein (HBc) in the viral life cycle: Implications for the development of HBc-targeting antivirals","volume":"149","author":"Diab","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.antiviral.2017.05.003","article-title":"Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome","volume":"144","author":"Chong","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.antiviral.2015.06.020","article-title":"Core protein: A pleiotropic keystone in the HBV lifecycle","volume":"121","author":"Zlotnick","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3319","DOI":"10.1128\/jvi.64.7.3319-3330.1990","article-title":"Hepatitis B virus nucleocapsid assembly: Primary structure requirements in the core protein","volume":"64","author":"Birnbaum","year":"1990","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4645","DOI":"10.1128\/jvi.63.11.4645-4652.1989","article-title":"A recombinant hepatitis B core antigen polypeptide with the protamine-like domain deleted self-assembles into capsid particles but fails to bind nucleic acids","volume":"63","author":"Gallina","year":"1989","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1128\/JVI.03235-13","article-title":"Nucleic acid chaperone activity associated with the arginine-rich domain of human hepatitis B virus core protein","volume":"88","author":"Chu","year":"2014","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Li, H.C., Huang, E.Y., Su, P.Y., Wu, S.Y., Yang, C.C., Lin, Y.S., Chang, W.C., and Shih, C. (2010). Nuclear export and import of human hepatitis B virus capsid protein and particles. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001162"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/978-1-4939-6700-1_5","article-title":"A Homokaryon Assay for Nucleocytoplasmic Shuttling Activity of HBV Core Protein","volume":"1540","author":"Yang","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"de Rocquigny, H., Rat, V., Pastor, F., Darlix, J.L., Hourioux, C., and Roingeard, P. (2020). Phosphorylation of the Arginine-Rich C-Terminal Domains of the Hepatitis B Virus (HBV) Core Protein as a Fine Regulator of the Interaction between HBc and Nucleic Acid. Viruses, 12.","DOI":"10.3390\/v12070738"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"38959","DOI":"10.1038\/srep38959","article-title":"HBV maintains electrostatic homeostasis by modulating negative charges from phosphoserine and encapsidated nucleic acids","volume":"6","author":"Su","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8124","DOI":"10.1128\/JVI.76.16.8124-8137.2002","article-title":"Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein","volume":"76","author":"Daub","year":"2002","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8754","DOI":"10.1128\/JVI.01343-14","article-title":"Phosphoacceptors threonine 162 and serines 170 and 178 within the carboxyl-terminal RRRS\/T motif of the hepatitis B virus core protein make multiple contributions to hepatitis B virus replication","volume":"88","author":"Jung","year":"2014","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9810","DOI":"10.1128\/JVI.79.15.9810-9820.2005","article-title":"Hepatitis B virus DNA replication is coordinated by core protein serine phosphorylation and HBx expression","volume":"79","author":"Melegari","year":"2005","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Heger-Stevic, J., Zimmermann, P., Lecoq, L., Bottcher, B., and Nassal, M. (2018). Hepatitis B virus core protein phosphorylation: Identification of the SRPK1 target sites and impact of their occupancy on RNA binding and capsid structure. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007488"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5830","DOI":"10.1128\/JVI.00394-16","article-title":"Cell-Free Hepatitis B Virus Capsid Assembly Dependent on the Core Protein C-Terminal Domain and Regulated by Phosphorylation","volume":"90","author":"Ludgate","year":"2016","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3389\/fmicb.2018.02661","article-title":"Post-translational Modification Control of HBV Biological Processes","volume":"9","author":"Yang","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1002\/hep.29236","article-title":"Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication","volume":"66","author":"Diab","year":"2017","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Langerova, H., Lubyova, B., Zabransky, A., Hubalek, M., Glendova, K., Aillot, L., Hodek, J., Strunin, D., Janovec, V., and Hirsch, I. (2020). Hepatitis B Core Protein Is Post-Translationally Modified through K29-Linked Ubiquitination. Cells, 9.","DOI":"10.3390\/cells9122547"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lubyova, B., Hodek, J., Zabransky, A., Prouzova, H., Hubalek, M., Hirsch, I., and Weber, J. (2017). PRMT5: A novel regulator of Hepatitis B virus replication and an arginine methylase of HBV core. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186982"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4149\/av_2020_207","article-title":"Posttranslational modifications of HBV core protein","volume":"64","author":"Lubyova","year":"2020","journal-title":"Acta Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.dnarep.2004.04.002","article-title":"PI 3-kinase related kinases: \u2018big\u2019 players in stress-induced signaling pathways","volume":"3","author":"Abraham","year":"2004","journal-title":"DNA Repair"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.dnarep.2009.04.006","article-title":"Common mechanisms of PIKK regulation","volume":"8","author":"Lovejoy","year":"2009","journal-title":"DNA Repair"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-12-380888-2.00003-0","article-title":"The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer","volume":"108","author":"Smith","year":"2010","journal-title":"Adv. Cancer Res."},{"key":"ref_29","first-page":"4255","article-title":"ATM and ATR signaling at a glance","volume":"128","author":"Awasthi","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.3748\/wjg.14.5059","article-title":"Cellular DNA repair cofactors affecting hepatitis B virus infection and replication","volume":"14","author":"Zhao","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.3748\/wjg.14.6163","article-title":"Ataxia telangiectasia-mutated-Rad3-related DNA damage checkpoint signaling pathway triggered by hepatitis B virus infection","volume":"14","author":"Zhao","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1099\/vir.0.000150","article-title":"Hepatitis B virus X protein activates the ATM-Chk2 pathway and delays cell cycle progression","volume":"96","author":"Kim","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kostyusheva, A., Brezgin, S., Bayurova, E., Gordeychuk, I., Isaguliants, M., Goptar, I., Urusov, F., Nikiforova, A., Volchkova, E., and Kostyushev, D. (2019). ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage. Viruses, 11.","DOI":"10.3390\/v11110997"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e03423-19","DOI":"10.1128\/mBio.03423-19","article-title":"Involvement of Host ATR-CHK1 Pathway in Hepatitis B Virus Covalently Closed Circular DNA Formation","volume":"11","author":"Luo","year":"2020","journal-title":"MBio"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/421486a","article-title":"DNA repair: Damage alert","volume":"421","author":"Bartek","year":"2003","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20532","DOI":"10.1074\/jbc.M113.467662","article-title":"4-Hydroxynonenal induces G2\/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)\/checkpoint kinase 1 (Chk1) signaling pathway","volume":"288","author":"Chaudhary","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1462-5822.2005.00677.x","article-title":"Interactions between DNA viruses, ND10 and the DNA damage response","volume":"8","author":"Everett","year":"2006","journal-title":"Cell Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.chom.2010.11.010","article-title":"Keeping viruses in Chk: DNA damage signaling puts the brakes on transformation","volume":"8","author":"Lilley","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-virology-092917-043534","article-title":"Virus DNA Replication and the Host DNA Damage Response","volume":"5","author":"Weitzman","year":"2018","journal-title":"Annu. Rev. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20160269","DOI":"10.1098\/rstb.2016.0269","article-title":"Take your PIKK: Tumour viruses and DNA damage response pathways","volume":"372","author":"Pancholi","year":"2017","journal-title":"Philos. Trans. R Soc. Lond B Biol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Xi, J., Luckenbaugh, L., and Hu, J. (2021). Multiple roles of PP2A binding motif in hepatitis B virus core linker and PP2A in regulating core phosphorylation state and viral replication. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009230"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1128\/JVI.01671-06","article-title":"Regulation of hepadnavirus reverse transcription by dynamic nucleocapsid phosphorylation","volume":"81","author":"Basagoudanavar","year":"2007","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1128\/jvi.74.10.4721-4728.2000","article-title":"Core protein phosphorylation modulates pregenomic RNA encapsidation to different extents in human and duck hepatitis B viruses","volume":"74","author":"Gazina","year":"2000","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1128\/JVI.01957-10","article-title":"The arginine clusters of the carboxy-terminal domain of the core protein of hepatitis B virus make pleiotropic contributions to genome replication","volume":"85","author":"Lewellyn","year":"2011","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13812","DOI":"10.1128\/JVI.78.24.13812-13818.2004","article-title":"Hepatitis B virus nucleocapsids formed by carboxy-terminally mutated core proteins contain spliced viral genomes but lack full-size DNA","volume":"78","author":"Kock","year":"2004","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1128\/JVI.79.3.1871-1887.2005","article-title":"Exposure of RNA templates and encapsidation of spliced viral RNA are influenced by the arginine-rich domain of human hepatitis B virus core antigen (HBcAg 165\u2013173)","volume":"79","author":"Chua","year":"2005","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10616","DOI":"10.1128\/JVI.00749-09","article-title":"Testing an electrostatic interaction hypothesis of hepatitis B virus capsid stability by using an in vitro capsid disassembly\/reassembly system","volume":"83","author":"Newman","year":"2009","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1128\/JVI.01666-09","article-title":"Testing the balanced electrostatic interaction hypothesis of hepatitis B virus DNA synthesis by using an in vivo charge rebalance approach","volume":"84","author":"Chua","year":"2010","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1128\/jvi.66.9.5232-5241.1992","article-title":"RNA- and DNA-binding activities in hepatitis B virus capsid protein: A model for their roles in viral replication","volume":"66","author":"Hatton","year":"1992","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10064","DOI":"10.1128\/JVI.01481-15","article-title":"Alteration of Mature Nucleocapsid and Enhancement of Covalently Closed Circular DNA Formation by Hepatitis B Virus Core Mutants Defective in Complete-Virion Formation","volume":"89","author":"Cui","year":"2015","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hu, Z., Ban, H., Zheng, H., Liu, M., Chang, J., and Guo, J.T. (2020). Protein phosphatase 1 catalyzes HBV core protein dephosphorylation and is co-packaged with viral pregenomic RNA into nucleocapsids. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008669"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"12237","DOI":"10.1128\/JVI.01218-12","article-title":"Cyclin-dependent kinase 2 phosphorylates s\/t-p sites in the hepadnavirus core protein C-terminal domain and is incorporated into viral capsids","volume":"86","author":"Ludgate","year":"2012","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Luo, J., Xi, J., Gao, L., and Hu, J. (2020). Role of Hepatitis B virus capsid phosphorylation in nucleocapsid disassembly and covalently closed circular DNA formation. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008459"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1248\/bpb.29.1810","article-title":"Biochemical characterization of suramin as a selective inhibitor for the PKA-mediated phosphorylation of HBV core protein in vitro","volume":"29","author":"Okabe","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1111\/j.1462-5822.2010.01444.x","article-title":"Inhibition of protein kinase C phosphorylation of hepatitis B virus capsids inhibits virion formation and causes intracellular capsid accumulation","volume":"12","author":"Wittkop","year":"2010","journal-title":"Cell Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1073\/pnas.97.2.871","article-title":"ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation","volume":"97","author":"Barlow","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10146","DOI":"10.1073\/pnas.95.17.10146","article-title":"ATM binds to beta-adaptin in cytoplasmic vesicles","volume":"95","author":"Lim","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0304-3940(98)00576-X","article-title":"Expression of the ataxia-telangiectasia gene (ATM) product in human cerebellar neurons during development","volume":"252","author":"Oka","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"34277","DOI":"10.1074\/jbc.274.48.34277","article-title":"Localization of a portion of extranuclear ATM to peroxisomes","volume":"274","author":"Watters","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1126\/science.1192912","article-title":"ATM activation by oxidative stress","volume":"330","author":"Guo","year":"2010","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"599048","DOI":"10.3389\/fcell.2020.599048","article-title":"ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?","volume":"8","author":"Stagni","year":"2020","journal-title":"Front Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Fu, X., Wan, S., Lyu, Y.L., Liu, L.F., and Qi, H. (2008). Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002009"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"371","DOI":"10.4161\/cc.6.3.3835","article-title":"Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: Relation to cell cycle phase","volume":"6","author":"Tanaka","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"35997","DOI":"10.1074\/jbc.M604149200","article-title":"A protease pathway for the repair of topoisomerase II-DNA covalent complexes","volume":"281","author":"Zhang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1002\/hep.27360","article-title":"Technical standards for hepatitis B virus X protein (HBx) research","volume":"61","author":"Slagle","year":"2015","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2257.2005.00728.x","article-title":"Haemophagocytic syndrome associated with hepatitis-B virus infection responding to etoposide","volume":"27","author":"Aleem","year":"2005","journal-title":"Clin. Lab. Haematol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1002\/cncr.20591","article-title":"Unexpectedly frequent hepatitis B reactivation by chemoradiation in postgastrectomy patients","volume":"101","author":"Cheng","year":"2004","journal-title":"Cancer"},{"key":"ref_69","first-page":"247","article-title":"Effect of cytotoxic chemotherapy on hepatitis B viral markers in patients with hepatocellular carcinoma","volume":"10","author":"Zaman","year":"1984","journal-title":"Clin. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1200\/JCO.2010.29.7531","article-title":"Prospective analysis of hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma after rituximab combination chemotherapy","volume":"28","author":"Niitsu","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_71","first-page":"38","article-title":"Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin\u2019s lymphoma","volume":"82","author":"Faggioli","year":"1997","journal-title":"Haematologica"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e21680","DOI":"10.1096\/fj.202002678R","article-title":"Extracellular vesicles activate ATM-Chk2 signaling pathway through the intercellular transfer of mitochondrial DNA in HBV-infected human hepatocytes","volume":"35","author":"Dansako","year":"2021","journal-title":"FASEB J."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/12\/2438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:39:55Z","timestamp":1760168395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/12\/2438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,5]]},"references-count":72,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["v13122438"],"URL":"https:\/\/doi.org\/10.3390\/v13122438","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,5]]}}}