Tags

Type your tag names separated by a space and hit enter

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage.
Viruses 2019; 11(11)V

Abstract

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.

Authors+Show Affiliations

National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia. kostyusheva_ap@mail.ru.National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia. Seegez@mail.ru. Institute of Immunology, Federal Medical Biological Agency, Moscow 115522, Russia. Seegez@mail.ru.NF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, Russia. p1ngv1n2009@yandex.ru. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia. p1ngv1n2009@yandex.ru.NF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, Russia. lab.gord@gmail.com. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia. lab.gord@gmail.com. Sechenov First Moscow State Medical University, Moscow 119146, Russia. lab.gord@gmail.com.NF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, Russia. maria.issagouliantis@rsu.lv. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 108819, Russia. maria.issagouliantis@rsu.lv. Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia. maria.issagouliantis@rsu.lv. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 76 Stockholm, Sweden. maria.issagouliantis@rsu.lv.Izmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, Russia. probirka@list.ru.Izmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, Russia. flanger.fx@mail.ru.Izmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, Russia. utkina.anastasia@gmail.com.Sechenov First Moscow State Medical University, Moscow 119146, Russia. az@rcvh.ru.National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia. dkostushev@gmail.com.National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia. vladimir.chulanov@rcvh.ru. Sechenov First Moscow State Medical University, Moscow 119146, Russia. vladimir.chulanov@rcvh.ru. Central Research Institute of Epidemiology, Moscow 111123, Russia. vladimir.chulanov@rcvh.ru.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31683589

Citation

Kostyusheva, Anastasiya, et al. "ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection Upon DNA Damage." Viruses, vol. 11, no. 11, 2019.
Kostyusheva A, Brezgin S, Bayurova E, et al. ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage. Viruses. 2019;11(11).
Kostyusheva, A., Brezgin, S., Bayurova, E., Gordeychuk, I., Isaguliants, M., Goptar, I., ... Chulanov, V. (2019). ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage. Viruses, 11(11), doi:10.3390/v11110997.
Kostyusheva A, et al. ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection Upon DNA Damage. Viruses. 2019 Oct 31;11(11) PubMed PMID: 31683589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage. AU - Kostyusheva,Anastasiya, AU - Brezgin,Sergey, AU - Bayurova,Ekaterina, AU - Gordeychuk,Ilya, AU - Isaguliants,Maria, AU - Goptar,Irina, AU - Urusov,Felix, AU - Nikiforova,Anastasiya, AU - Volchkova,Elena, AU - Kostyushev,Dmitry, AU - Chulanov,Vladimir, Y1 - 2019/10/31/ PY - 2019/09/02/received PY - 2019/10/17/revised PY - 2019/10/30/accepted PY - 2019/11/6/entrez KW - ATM KW - ATR KW - CRISPR/Cas9 KW - CRISPRa KW - DNA damage KW - HBV reactivation KW - dCas9 KW - phosphorylated H2AX KW - replication KW - shRNA KW - yH2AX JF - Viruses JO - Viruses VL - 11 IS - 11 N2 - 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. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/31683589/ATM_and_ATR_Expression_Potentiates_HBV_Replication_and_Contributes_to_Reactivation_of_HBV_Infection_upon_DNA_Damage L2 - http://www.mdpi.com/resolver?pii=v11110997 DB - PRIME DP - Unbound Medicine ER -