Promyelocytic Leukemia Nuclear Bodies Link the DNA Damage Repair Pathway with Hepatitis B Virus Replication: Implications for Hepatitis B Virus Exacerbation during Chemotherapy and Radiotherapy

Chung, Yih-Lin; Tsai, Tzung-Yuan

doi:10.1158/1541-7786.mcr-09-0112

Cited by 31 publications

(37 citation statements)

References 37 publications

(64 reference statements)

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“…Various aspects of HBV expression were reported to impact on DNA repair [139,140,141,142,143,144,145], but most attention was paid to HBx, owing to its suspected role as an oncogene. Notably, HBx is now rather seen as a cofactor enhancing the transforming activity of true carcinogens [29,146,147].…”

Section: Evidence For a Connection Between Hbv And The Host Dna Damentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

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Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.

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Section: Evidence For a Connection Between Hbv And The Host Dna Damentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

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“…During chemotherapy and radiotherapy, PML in PML-NBs could link the DNA damage response to HBV replication. Additionally, PML may interact with HBV-core and HDAC1 on the promoter of the covalently closed circular HBV DNA basal core [62]. In mammals, Sirtuin 6 (SIRT6), a mammalian homolog of the yeast Sir2 deacetylase, is required for genome instability.…”

Section: Modification Of Chromatin-remodeling Factors Is Linked Tomentioning

confidence: 99%

Connecting Chromatin Modifying Factors to DNA Damage Response

Lai

Liu

et al. 2013

IJMS

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Cells are constantly damaged by factors that can induce DNA damage. Eukaryotic cells must rapidly load DNA repair proteins onto damaged chromatin during the DNA damage response (DDR). Chromatin-remodeling complexes use the energy from ATP hydrolysis to remodel nucleosomes and have well-established functions in transcription. Emerging lines of evidence indicate that chromatin-remodeling complexes are important and may remodel nucleosomes during DNA damage repair. New studies also reveal that ATP-dependent chromatin remodeling is involved in cell cycle progression, signal transduction pathways, and interaction and modification of DDR-related proteins that are specifically and intimately connected with the process of DNA damage. This article summarizes the recent advances in our understanding of the interplay between chromatin remodeling and DNA damage response.

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“…It is not known if Smc5/6 localizes to ND10 in non-transformed cells, such as primary human hepatocytes (PHH). Similarly, although HBV DNA has been reported to localize to PML foci in a stably HBV-producing hepatoma-derived cell line [23], the role of ND10 in the viral replication cycle has not been studied in HBV-infected PHH.…”

Section: Introductionmentioning

confidence: 99%

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

et al. 2017

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The structural maintenance of chromosome 5/6 complex (Smc5/6) is a restriction factor that represses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing HBV X protein (HBx), which targets Smc5/6 for degradation. However, the mechanism by which Smc5/6 suppresses HBV transcription and how HBx is initially expressed is not known. In this study we characterized viral kinetics and the host response during HBV infection of primary human hepatocytes (PHH) to address these unresolved questions. We determined that Smc5/6 localizes with Nuclear Domain 10 (ND10) in PHH. Co-localization has functional implications since depletion of ND10 structural components alters the nuclear distribution of Smc6 and induces HBV gene expression in the absence of HBx. We also found that HBV infection and replication does not induce a prominent global host transcriptional response in PHH, either shortly after infection when Smc5/6 is present, or at later times post-infection when Smc5/6 has been degraded. Notably, HBV and an HBx-negative virus establish high level infection in PHH without inducing expression of interferon-stimulated genes or production of interferons or other cytokines. Our study also revealed that Smc5/6 is degraded in the majority of infected PHH by the time cccDNA transcription could be detected and that HBx RNA is present in cell culture-derived virus preparations as well as HBV patient plasma. Collectively, these data indicate that Smc5/6 is an intrinsic antiviral restriction factor that suppresses HBV transcription when localized to ND10 without inducing a detectable innate immune response. Our data also suggest that HBx protein may be initially expressed by delivery of extracellular HBx RNA into HBV-infected cells.

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Promyelocytic Leukemia Nuclear Bodies Link the DNA Damage Repair Pathway with Hepatitis B Virus Replication: Implications for Hepatitis B Virus Exacerbation during Chemotherapy and Radiotherapy

Cited by 31 publications

References 37 publications

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Connecting Chromatin Modifying Factors to DNA Damage Response

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

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