HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA.
Animals
Carcinoma, Hepatocellular
/ complications
Cell Cycle Proteins
/ adverse effects
Chromosomal Proteins, Non-Histone
/ adverse effects
Disease Models, Animal
Liver
/ drug effects
Liver Neoplasms
/ complications
Mice
Recombinational DNA Repair
/ drug effects
Statistics, Nonparametric
Trans-Activators
/ drug effects
Viral Regulatory and Accessory Proteins
/ drug effects
DDB1
DNA damage
HBx
Nitazoxanide
cccDNA
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
03
03
2021
revised:
25
07
2021
accepted:
11
08
2021
pubmed:
4
9
2021
medline:
16
2
2022
entrez:
3
9
2021
Statut:
ppublish
Résumé
HBV causes hepatocellular carcinoma (HCC). While it was recently shown that the ability of HBV X protein (HBx) to impair the Smc5/6 (structural maintenance of chromosome 5/6) complex is important for viral transcription, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear. Degradation of the Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx. HBx-triggered degradation of the Smc5/6 complex causes impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the CRISPR-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells. Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs. The hepatitis B virus expresses a regulatory protein called HBV X protein (or HBx). This protein degrades the Smc5/6 complex in human hepatocytes, which is essential for viral replication. We found that this process also plays a key role in the accumulation of DNA damage, which contributes to HBx-mediated tumorigenesis.
Sections du résumé
BACKGROUND & AIMS
HBV causes hepatocellular carcinoma (HCC). While it was recently shown that the ability of HBV X protein (HBx) to impair the Smc5/6 (structural maintenance of chromosome 5/6) complex is important for viral transcription, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear.
METHODS
Degradation of the Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx.
RESULTS
HBx-triggered degradation of the Smc5/6 complex causes impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the CRISPR-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells.
CONCLUSIONS
Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs.
LAY SUMMARY
The hepatitis B virus expresses a regulatory protein called HBV X protein (or HBx). This protein degrades the Smc5/6 complex in human hepatocytes, which is essential for viral replication. We found that this process also plays a key role in the accumulation of DNA damage, which contributes to HBx-mediated tumorigenesis.
Identifiants
pubmed: 34478763
pii: S0168-8278(21)02005-5
doi: 10.1016/j.jhep.2021.08.010
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
SMC5 protein, human
0
SMC6 protein, human
0
Trans-Activators
0
Viral Regulatory and Accessory Proteins
0
hepatitis B virus X protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
53-62Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.