The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis
Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently, it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into the hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertio...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14849 |
| _version_ | 1797575747902111744 |
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| author | Tomasz I. Michalak |
| author_facet | Tomasz I. Michalak |
| author_sort | Tomasz I. Michalak |
| collection | DOAJ |
| description | Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently, it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into the hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions, suggesting a mechanism for spontaneous HBV DNA dispersal throughout the hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions, indicating their creation by non-homologous end-joining (NHEJ). Their formation coincided with the robust oxidative damage of hepatocyte DNA. This was associated with the activation of poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair, as reflected by the augmented transcription of PARP1 and XRCC1; the PARP1 binding partner OGG1, a responder to oxidative DNA damage; and increased activity of NAD<sup>+</sup>, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains the HTJ format of the initial merges. The findings show that HBV and WHV are immediate inducers of oxidative DNA damage and hijack dsDNA repair to integrate into the hepatocyte genome, and through this mechanism, they may initiate pro-oncogenic processes. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis. |
| first_indexed | 2024-03-10T21:42:42Z |
| format | Article |
| id | doaj.art-5a3dd499a8bc4f128c1134aee94bb2f3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:42:42Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5a3dd499a8bc4f128c1134aee94bb2f32023-11-19T14:31:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191484910.3390/ijms241914849The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular OncogenesisTomasz I. Michalak0Molecular Virology and Hepatology Research Group, Division of BioMedical Science, Faculty of Medicine, Health Science Center, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, CanadaHepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently, it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into the hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions, suggesting a mechanism for spontaneous HBV DNA dispersal throughout the hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions, indicating their creation by non-homologous end-joining (NHEJ). Their formation coincided with the robust oxidative damage of hepatocyte DNA. This was associated with the activation of poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair, as reflected by the augmented transcription of PARP1 and XRCC1; the PARP1 binding partner OGG1, a responder to oxidative DNA damage; and increased activity of NAD<sup>+</sup>, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains the HTJ format of the initial merges. The findings show that HBV and WHV are immediate inducers of oxidative DNA damage and hijack dsDNA repair to integrate into the hepatocyte genome, and through this mechanism, they may initiate pro-oncogenic processes. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.https://www.mdpi.com/1422-0067/24/19/14849HBVwoodchuck hepatitis virusearly hepadnavirus–host DNA integrationvirus-induced oxidative DNA damagedsDNA repairretrotransposons |
| spellingShingle | Tomasz I. Michalak The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis International Journal of Molecular Sciences HBV woodchuck hepatitis virus early hepadnavirus–host DNA integration virus-induced oxidative DNA damage dsDNA repair retrotransposons |
| title | The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis |
| title_full | The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis |
| title_fullStr | The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis |
| title_full_unstemmed | The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis |
| title_short | The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis |
| title_sort | initial hepatitis b virus hepatocyte genomic integrations and their role in hepatocellular oncogenesis |
| topic | HBV woodchuck hepatitis virus early hepadnavirus–host DNA integration virus-induced oxidative DNA damage dsDNA repair retrotransposons |
| url | https://www.mdpi.com/1422-0067/24/19/14849 |
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