ATM and atr expression potentiates hbv replication and contributes to reactivation of hbv infection upon DNA damage

Anastasiya Kostyusheva, Sergey Brezgin, Ekaterina Bayurova, Ilya Gordeychuk, Maria Isaguliants, Irina Goptar, Felix Urusov, Anastasiya Nikiforova, Elena Volchkova, Dmitry Kostyushev, Vladimir Chulanov

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
1 Downloads (Pure)

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.

Original languageEnglish
Article number997
JournalViruses
Volume11
Issue number11
DOIs
Publication statusPublished - 31 Oct 2019

Keywords

  • Atm
  • Atr
  • Crispr/Cas9
  • Crispra
  • Dcas9
  • DNA damage
  • HBV reactivation
  • Phosphorylated H2AX
  • Replication
  • Shrna
  • Yh2Ax

Field of Science

  • 3.3 Health sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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