ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage
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...
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| Format: | Article |
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MDPI AG
2019-10-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/11/11/997 |
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| author | Anastasiya Kostyusheva Sergey Brezgin Ekaterina Bayurova Ilya Gordeychuk Maria Isaguliants Irina Goptar Felix Urusov Anastasiya Nikiforova Elena Volchkova Dmitry Kostyushev Vladimir Chulanov |
| author_facet | Anastasiya Kostyusheva Sergey Brezgin Ekaterina Bayurova Ilya Gordeychuk Maria Isaguliants Irina Goptar Felix Urusov Anastasiya Nikiforova Elena Volchkova Dmitry Kostyushev Vladimir Chulanov |
| author_sort | Anastasiya Kostyusheva |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T21:57:25Z |
| format | Article |
| id | doaj.art-795411452e6b42cab8b46cca5a17cec3 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-11T21:57:25Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-795411452e6b42cab8b46cca5a17cec32022-12-22T00:49:15ZengMDPI AGViruses1999-49152019-10-01111199710.3390/v11110997v11110997ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA DamageAnastasiya Kostyusheva0Sergey Brezgin1Ekaterina Bayurova2Ilya Gordeychuk3Maria Isaguliants4Irina Goptar5Felix Urusov6Anastasiya Nikiforova7Elena Volchkova8Dmitry Kostyushev9Vladimir Chulanov10National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, RussiaNational Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, RussiaNF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, RussiaNF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, RussiaNF Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, RussiaIzmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, RussiaIzmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, RussiaIzmerov Research Institute of Occupational Health, Gene Engineering and Biotechnology, Moscow 105275, RussiaSechenov First Moscow State Medical University, Moscow 119146, RussiaNational Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, RussiaNational Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, RussiaChronic 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.https://www.mdpi.com/1999-4915/11/11/997hbv reactivationreplicationdna damageatmatrphosphorylated h2axyh2axshrnacrispr/cas9crispradcas9 |
| spellingShingle | Anastasiya Kostyusheva Sergey Brezgin Ekaterina Bayurova Ilya Gordeychuk Maria Isaguliants Irina Goptar Felix Urusov Anastasiya Nikiforova Elena Volchkova Dmitry Kostyushev Vladimir Chulanov ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage Viruses hbv reactivation replication dna damage atm atr phosphorylated h2ax yh2ax shrna crispr/cas9 crispra dcas9 |
| title | ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage |
| title_full | ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage |
| title_fullStr | ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage |
| title_full_unstemmed | ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage |
| title_short | ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage |
| title_sort | atm and atr expression potentiates hbv replication and contributes to reactivation of hbv infection upon dna damage |
| topic | hbv reactivation replication dna damage atm atr phosphorylated h2ax yh2ax shrna crispr/cas9 crispra dcas9 |
| url | https://www.mdpi.com/1999-4915/11/11/997 |
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