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

Abstract

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.

Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment

“…The hepatitis B virus encodes an oncoprotein, Hepatitis B x protein (HBx) that can hijack the Cul4-Ddb1 machinery by displacing WDR70 (and likely other DCAFs) to form viral CRL4 HBx . Disassembly of the CRL4 WDR70 complex by HBx compromises DNA end resection and results in HR deficiency (Ren et al, 2019). Understanding the target of the CRL4 WDR70 machinery may provide insights into new targets for sensitizing cancer cells to IR.…”

Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma

“…HBV infection can promote the proliferation, angiogenesis, and invasion of HCC 10 - 13 . HBV-encoded X protein (HBx), encoded by covalently closed circular DNA (cccDNA) from HBV, is an essential gene for the emergence of HBV-associated HCC 14 . As a multifunctional protein, HBx has been reported to regulate the transcription of target genes by affecting intracellular signal transduction and transcription factors 15 , by interfering with the natural function and characteristics of host cells 16 .…”

Synthetic lethality between TP53 and ENDOD1

“…Olaparib 2 and Talazoparib 3 ) enzymatically inactivate and trap PARPs to DNA breaks, necessitating functional homologous recombination (HR) to avoid cytotoxicity 4 . During a characterization of PARPi-induced DNA damage responses in the presence and absence of the Hepatitis B virus protein HBx 5 , which induces a HRD by depleting CUL4 WDR70 , we detected an increase in endonuclease domain-containing protein 1 (ENDOD1) peptides following six days of Olaparib treatment (data not shown and Supplementary Figure 1).…”