ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage
ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage
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DOI：
10.3390/v11110997
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发表时间：
2019-11-01
期刊：
影响因子：
4.7
通讯作者：
Chulanov, Vladimir
中科院分区：
文献类型：
--
作者：
Kostyusheva, Anastasiya;Brezgin, Sergey;Chulanov, Vladimir
慢性乙型肝炎病毒感染（Chronic hepatitis B virus infection，CHB）是由乙型肝炎病毒（hepatitis B virus，HBV）引起的世界上最常见的病毒感染之一。HBV感染的再激活是在接受化疗或其他药物治疗的CHB患者中观察到的危及生命的情况。虽然HBV再激活通常归因于免疫抑制，但长期以来一直怀疑其他因素也起作用，包括响应DNA损伤而激活的细胞内信号传导。我们研究了DNA损伤因子（多柔比星和过氧化氢）对HBV再激活/复制和随后的DNA损伤反应的影响。观察到剂量依赖性激活的HBV复制反应阿霉素和过氧化氢，这与共济失调毛细血管扩张突变（ATM）和ATM和RAD 3相关（ATR）激酶的mRNA水平显着升高。通过shRNAs下调ATM或ATR的表达显著降低了HBV RNA和DNA的水平。相反，使用CRISPRa的ATM或ATR的转录激活显著增加HBV复制。我们的结论是，ATM和ATR是必不可少的HBV复制。此外，DNA损伤导致ATM和ATR转录的激活，导致HBV复制的重新激活。
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.