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Open AccessArticle

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

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National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia
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Institute of Immunology, Federal Medical Biological Agency, Moscow 115522, Russia
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NF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, Russia
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Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia
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Sechenov First Moscow State Medical University, Moscow 119146, Russia
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Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia
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Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
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Izmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, Russia
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Central Research Institute of Epidemiology, Moscow 111123, Russia
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(11), 997; https://doi.org/10.3390/v11110997
Received: 2 September 2019 / Revised: 17 October 2019 / Accepted: 30 October 2019 / Published: 31 October 2019
(This article belongs to the Special Issue Hepatitis B Virus Reactivation)
Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication. View Full-Text
Keywords: HBV reactivation; replication; DNA damage; ATM; ATR; phosphorylated H2AX; yH2AX; shRNA; CRISPR/Cas9; CRISPRa; dCas9 HBV reactivation; replication; DNA damage; ATM; ATR; phosphorylated H2AX; yH2AX; shRNA; CRISPR/Cas9; CRISPRa; dCas9
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Kostyusheva, A.; Brezgin, S.; Bayurova, E.; Gordeychuk, I.; Isaguliants, M.; Goptar, I.; Urusov, F.; Nikiforova, A.; Volchkova, E.; Kostyushev, D.; Chulanov, V. ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage. Viruses 2019, 11, 997.

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