ArticleHepatology communications2022
Inhibition of nonhomologous end joining-mediated DNA repair enhances anti-HBV CRISPR therapy.
Article in Hepatology communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
10 citing papers in PubMed, 10 citations in OpenAlex.
- Review
- DOCK11 promotes HBV cccDNA formation through a PARP1-dependent mechanism.Microbiology spectrum · 2026Article
- PARPs and PARP inhibitors: molecular mechanisms and clinical applications.Molecular biomedicine · 2025Review
- Genomic medicine in hepatology: mechanisms and liver treatment strategies.Molecular medicine (Cambridge, Mass.) · 2025Review
- Genome-wide loss-of-function genetic screen identifies INSIG2 as the vulnerability of hepatitis B virus-integrated hepatoma cells.Cancer science · 2024Article
- The potential of HBV cure: an overview of CRISPR-mediated HBV gene disruption.Frontiers in genome editing · 2024Review
- Review
- CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death.Scientific reports · 2023Article
- Gene Editing Technologies to Target HBV cccDNA.Viruses · 2022Review
- Inhibition of nonhomologous end joining-mediated DNA repair enhances anti-HBV CRISPR therapy.Hepatology communications · 2022Article
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current anti-hepatitis B virus (HBV) therapies have little effect on covalently closed circular DNA (cccDNA) and fail to eliminate HBV. The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system has been reported to directly target cccDNA and exert antiviral effects. In this study, we hypothesized that the inhibition of the DNA repair machinery, which is important for the repair of CRISPR-induced double-strand breaks, may enhance the effect of CRISPR targeting cccDNA, and we investigated the antiviral effect of potential combination therapy. The antiviral effect of CRISPR targeting cccDNA (HBV-CRISPR) was evaluated in HBV-susceptible HepG2-hNTCP-C4 cells expressing Cas9 (HepG2-hNTCP-C4-iCas9) or primary human hepatocytes (PHHs) expressing Cas9. Following HBV infection, HBV-CRISPR reduced cccDNA levels, accompanied by decreases in pregenomic RNA (pgRNA) levels and supernatant HBV DNA, hepatitis B surface antigen and hepatitis B e antigen levels in HepG2-hNTCP-C4-iCas9 cells, and PHHs. HBV-CRISPR induced indel formation in cccDNA and up-regulated poly(adenosine diphosphate ribose) polymerase (PARP) activity in HBV-infected HepG2-hNTCP-C4-iCas9 cells. The suppression of PARP2-Histone PARylation factor 1 (HPF1) (involved in the initial step of DNA repair) with small interfering RNA (siRNA) targeting either PARP2 or HPF1 increased the reduction in pgRNA and cccDNA by HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells. The suppression of DNA Ligase 4 (LIG4) (essential for nonhomologous end joining [NHEJ]) but not breast cancer susceptibility gene (BRCA) (essential for homologous recombination) enhanced the antiviral effect of HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells. Finally, the clinically available PARP inhibitor olaparib increased the reductions in pgRNA and cccDNA levels induced by HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells and PHHs. Conclusion: The suppression of the NHEJ-mediated DNA repair machinery enhances the effect of CRISPR targeting cccDNA. The combination of CRISPR and olaparib may represent a therapy for HBV elimination.
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