Hepatitis B virus pre-S2 mutant large surface protein inhibits DNA double-strand break repair and leads to genome instability in hepatocarcinogenesis

The Journal of Pathology
Yi-Hsuan HsiehWenya Huang

Abstract

Although hepatitis B virus (HBV) has been established to cause hepatocellular carcinoma (HCC), the exact mechanism remains to be clarified. Type II ground glass hepatocytes (GGHs) harbouring the HBV pre-S2 mutant large surface protein (LHBS) have been recognized as a morphologically distinct hallmark of HCC in the advanced stages of chronic HBV infection. Considering its preneoplastic nature, we hypothesized that type II GGH may exhibit high genomic instability, which is important for the carcinogenic process in chronic HBV carriers. In this study we found that pre-S2 mutant LHBS directly interacted with importin α1, the key factor that recognizes cargos undergoing nuclear transportation mediated by the importin α/β-associated nuclear pore complex (NPC). By interacting with importin α1, which inhibits its function as an NPC factor, pre-S2 mutant LHBS blocked nuclear transport of an essential DNA repair and recombination factor, Nijmegen breakage syndrome 1 (NBS1), upon DNA damage, thereby delaying the formation of nuclear foci at the sites of DNA double-strand breaks (DSBs). Pre-S2 mutant LHBS was also found to block NBS1-mediated homologous recombination repair and induce multi-nucleation of cells. In addition, pre-S2 mutant L...Continue Reading

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Citations

Jan 13, 2016·Molecular Therapy : the Journal of the American Society of Gene Therapy·Qianshan DingGuoan Xiang
Oct 20, 2017·Viruses·Andoni Gómez-Moreno, Urtzi Garaigorta
May 4, 2018·Alimentary Pharmacology & Therapeutics·C-L Lin, J-H Kao
Jan 20, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Chia-Jui YenWenya Huang
Sep 25, 2019·International Journal of Molecular Sciences·Daniela Bender, Eberhard Hildt
May 30, 2020·Nature Reviews. Gastroenterology & Hepatology·Peter A RevillMargaret Littlejohn
Jan 29, 2016·World Journal of Gastroenterology : WJG·Caecilia H C SukowatiClaudio Tiribelli
Mar 4, 2021·Viruses·Teresa Pollicino, Giuseppe Caminiti
Mar 27, 2021·Cellular and Molecular Gastroenterology and Hepatology·Yuri ChurinElke Roeb
Sep 10, 2020·JHEP Reports : Innovation in Hepatology·Damien CohenIsabelle Chemin

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