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Kinetics of DNA damage repair response accompanying initial hepadnavirus-host genomic integration in woodchuck hepatitis virus infection of hepatocyte.
Cancer Genetics ( IF 1.9 ) Pub Date : 2020-02-05 , DOI: 10.1016/j.cancergen.2020.02.001
Ranjit Chauhan 1 , Tomasz I Michalak 1
Affiliation  

Mechanism of initial hepatitis B virus (HBV) integrations and kinetics of DNA repair immediately after infection remain essentially unknown impairing understanding of hepadnaviral oncogenesis. WCM260 hepatocytes susceptible to HBV-compatible woodchuck hepatitis virus (WHV) were examined from 15 min to 72 h post-infection (p.i.). WHV strongly induced reactive oxygen species (ROS), transiently inducible nitric oxide (iNOS) and DNA damage from 15 min p.i. All initial WHV-host fusions had the head-to-tail format indicating their formation by non-homologous end joining (NHEJ). Transcription of poly(ADP-ribose) polymerase 1 (PARP1) and X-ray repair cross-complementing protein 1 (XRCC1), the PARP1 binding partner, were induced in 30 min p.i. and that of 8-oxyguanine DNA glycosylse (OGG1) responding to oxidative DNA damage at 12 h p.i. Nicotinamide adenine dinucleotide (NAD+), a marker of PARP1 activation, and heme oxygenase-1 (HO1), an indicator of pro-oxidative stress, were significantly augmented from 15-30 min p.i. Additionally, PARP1 cleavage activity was evident from 30 min p.i. confirming that PARP1-mediated DNA repair became operational almost instatly after hepatocyte contact with virus. By applying complementary approaches, the study showed that initial WHV integration was due to virus-induced oxidative DNA damage and implied that the NHEJ PARP1-dependent repair pathway determined format of the first virus-host DNA junctions.



中文翻译:

在土拨鼠肝炎病毒感染肝细胞中伴随最初的嗜肝DNA病毒-宿主基因组整合而伴随的DNA损伤修复反应的动力学。

最初的乙型肝炎病毒(HBV)整合机制和感染后立即修复DNA的动力学仍然未知,这削弱了对肝炎病毒致癌性的了解。在感染后(pi)的15分钟至72小时内检查了易感染HBV的土拨鼠肝炎病毒(WHV)的WCM260肝细胞。WHV强烈诱导活性氧(ROS),瞬时诱导型一氧化氮(iNOS)和pi从15分钟起对DNA的损害所有最初的WHV-宿主融合体均具有从头到尾的形式,表明它们是通过非同源末端连接(NHEJ)形成的。聚(ADP-核糖)聚合酶1(PARP1)和X射线修复交叉互补蛋白1(XRCC1)(PARP1结合伴侣)的转录在pi的30分钟内被诱导,而8-氧鸟嘌呤DNA糖基化酶(OGG1)响应感染后12 h对DNA的氧化损伤PARP1活化的标记+)和血红素加氧酶-1(HO1)(促氧化应激的指标)从pi的15-30分钟开始显着增强。此外,从pi的30 min开始,PARP1的裂解活性明显,证实了PARP1肝细胞与病毒接触后,介导的DNA修复几乎不起作用。通过应用互补方法,研究表明最初的WHV整合是由于病毒引起的氧化DNA损伤,并且暗示NHEJ PARP1依赖性修复途径决定了第一个病毒-宿主DNA连接的形式。

更新日期:2020-02-05
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