HBx affects CUL4–DDB1 function in both positive and negative manners

Guo, Liandi; Wang, Xiaobo; Ren, Laifeng; Zeng, Ming; Wang, Si; Weng, Yuding; Tang, Zizhi; Wang, Xin; Tang, Yezhong; Hu, Huaidong; Li, Mingyuan; Zhang, Chongjie; Liu, Cong

doi:10.1016/j.bbrc.2014.07.019

Cited by 19 publications

(20 citation statements)

References 24 publications

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“…In contrast, the interaction of HBx with DDB1 or WDR5 might interfere with the interaction between DDB1 and WDR5, providing protective effects against WDR5 degradation by DDB1, as observed in our study. It's interesting to note that HBx can exert its function on the ubiquitin protein degradation system in either a positive or negative manner . Many studies have demonstrated that HBx can interact with and hijack ubiquitin ligase to target proteins for degradation; yet, other studies have found that HBx can also inhibit ubiquitin ligase and thus stabilize target proteins, such as Pituitary Tumor‐Transforming Gene 1, protein arginine N‐methyltransferase 1, and Amplified in Breast Cancer 1, as we found for WDR5 in this study.…”

Section: Discussionsupporting

confidence: 60%

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein

Gao

Jia²,

Tian

et al. 2020

Hepatology

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Background and Aims Cancer is typically considered as a genetic and epigenetic disease. Although numerous studies have indicated that an aberrant structure, function, or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)‐induced hepatocellular carcinoma (HCC) remains unknown. Approach and Results In this study, we found that the WD repeat domain 5 protein (WDR5)—a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification—is highly expressed in HBV‐related HCC and promotes HCC development. WDR5 plays a critical role in HBV‐driven cell proliferation and tumor growth in mice, and the WDR5‐0103 small‐molecule inhibitor of WDR5 activity compromises HBV‐ and hepatitis B x protein (HBx)‐driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve HBx through its stabilization of the WDR5 protein by inhibiting the interaction between the damage‐specific DNA‐binding protein 1/cullin‐4 and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome wide and promotes genome‐wide H3K4me3 modification by means of WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5 through its α‐helix domain. WDR5 was also found to promote HBV transcription through H3K4 modification of covalently closed circular DNA minichromosome, and WDR5‐0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor‐promoting function in a WDR5‐dependent manner. Conclusions Our data reveals that WDR5 is a key epigenetic determinant of HBV‐induced tumorigenesis and that the HBx‐WDR5‐H3K4me3 axis may be a potential therapeutic target in HBV‐induced liver pathogenesis.

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Section: Discussionsupporting

confidence: 60%

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein

Gao

Jia²,

Tian

et al. 2020

Hepatology

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“…To exclude this possibility and extend our observations to the circumstances of natural viral infection, we present two lines of evidence to establish that the HBV‐induced resection and HR defects represent a generalized phenomenon. First, we show that the defects in RPA phosphorylation and RAD51 IR‐induced foci (IRIF) hold true in an independently derived HBV‐positive cell line (T43) that was generated by integrating viral genomes into normal hepatic L02 cells (Fig. D,F; Supporting Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This poses the question as to whether the modulation of resection benefits viral replication. In previous work we showed that ablating DDB1 inhibited viral production and gene expression of HBV, indicating that DDB1 is required for viral production . Our preliminary data also suggest that loss of WDR70 facilitates viral replication (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

et al. 2019

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Chronic infection of hepatitis B virus (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein, hepatitis B x protein (HBx), that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications, and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits antiresection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This antiresection activity occurs in primary human hepatocytes undergoing a natural viral infection–replication cycle as well as in cells with integrated HBV genomes. Among the seven HBV‐encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A–damage‐specific DNA binding protein 1–RING type of E3 ligase, CRL4 WDR70 , through its H‐box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 at double‐strand breaks, thus reducing the efficiency of long‐range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4 WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrate that lack of H2B monoubiquitylation is manifest in human HBV‐associated HCC when compared with HBV‐free HCC, implying corresponding defects of epigenetic regulation and end resection. Conclusion: The antiresection activity of HBx induces an HR defect and genomic instability and contributes to tumorigenesis of host hepatocytes.

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“…DDB1 was first implicated in viral pathogenesis when it was shown to interact with h epatitis B protein X (HBx), which competitively inhibits DDB2 from interacting with DDB1 by binding to the same pocket (Bontron, 2002; Lee et al, 1995; Li et al, 2010). Although the precise mechanisms have not been uncovered, DDB1–HBx interactions can promote viral replication, induce cell death and potentially disrupt endogenous CRL4 activity (Guo et al, 2014; Leupin et al, 2005). …”

Section: Clinical Relevancementioning

confidence: 99%

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Hannah

Zhou

2015

Gene

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The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.

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HBx affects CUL4–DDB1 function in both positive and negative manners

Cited by 19 publications

References 24 publications

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein

The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

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