Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Lluesma, Silvia Martin; Schaeffer, Céline; Robert, Eva; Breugel, Pieter C. van; Leupin, Olivier; Hantz, Olivier; Strubin, Michel

doi:10.1002/hep.22542

Cited by 96 publications

(75 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, in addition to binding DDB1, the SV5 V protein causes cell cycle alterations, including G 2 /M arrest, as a consequence of its association with DDB1, which is similar to our observations with UL35 (53). In addition, the hepatitis B virus and woodchuck hepatitis virus X proteins both bind to DDB1, and expression is associated with altered progression through S phase, genomic instability, and apoptosis (4,13,50,61). Another herpesvirus, murine gamma herpesvirus 68 (MHV68), also targets DDB1 through its M2 latency protein, which interacts with DDB1 as well as ATM and inhibits DNA damage-induced apoptosis (52).…”

Section: Discussionsupporting

confidence: 87%

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Salsman

Jagannathan

Paladino

et al. 2012

J Virol

View full text Add to dashboard Cite

Human cytomegalovirus infections involve the extensive modification of host cell pathways, including cell cycle control, the regulation of the DNA damage response, and averting promyelocytic leukemia (PML)-mediated antiviral responses. The UL35 gene from human cytomegalovirus is important for viral gene expression and efficient replication and encodes two proteins, UL35 and UL35a, whose mechanism of action is not well understood. Here, affinity purification coupled with mass spectrometry was used to identify previously unknown human cellular targets of UL35 and UL35a. We demonstrate that both viral proteins interact with the ubiquitin-specific protease USP7, and that UL35 expression can alter USP7 subcellular localization. In addition, UL35 (but not UL35a) was found to associate with three components of the Cul4 DCAF1 E3 ubiquitin ligase complex (DCAF1, DDB1, and DDA1) previously shown to be targeted by the HIV-1 Vpr protein. The coimmunoprecipitation and immunofluorescence microscopy of DCAF1 mutants revealed that the C-terminal region of DCAF1 is required for association with UL35 and mediates the dramatic relocalization of DCAF1 to UL35 nuclear bodies, which also contain conjugated ubiquitin. As previously reported for the Vpr-DCAF1 interaction, UL35 (but not UL35a) expression resulted in the accumulation of cells in the G 2 phase of the cell cycle, which is typical of a DNA damage response, and activated the G 2 checkpoint in a DCAF1-dependent manner. In addition, UL35 (but not UL35a) induced ␥-H2AX and 53BP1 foci, indicating the activation of DNA damage and repair responses. Therefore, the identified interactions suggest that UL35 can contribute to viral replication through the manipulation of host responses.H uman cytomegalovirus (HCMV) is a member of the betaherpesvirus subfamily and consists of an ϳ230-kbp doublestranded DNA genome encased in an icosahedral capsid, surrounded by a proteinaceous matrix (tegument) layer and a host-derived lipid bilayer containing several viral glycoproteins. HCMV can establish both lytic and latent infections in human hosts yet causes little to no adverse effect in healthy adults. However, lytic HCMV replication is associated with significant disease and sometimes death in immunocompromised hosts, typically transplant recipients, neonates, and people with AIDS (16). HCMV encodes more than 200 viral proteins, although many remain poorly or completely uncharacterized (77). The expression of specific viral proteins is temporally controlled during the three general phases of the lytic replication cycle: the immediate-early (IE), early, and late phases (73). In addition, in the pre-IE phase, tegument-derived viral proteins are delivered to the host cell preformed and therefore can act before viral gene expression occurs to manipulate cells in ways that favor lytic replication (38).Herpesvirus infections are associated with the extensive manipulation of host cell processes, including the control of the cell cycle, apoptosis, immune activation, and the DNA damage response (DDR) (...

show abstract

Section: Discussionsupporting

confidence: 87%

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Salsman

Jagannathan

Paladino

et al. 2012

J Virol

View full text Add to dashboard Cite

show abstract

“…DSBs result in activation of the ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) kinases, which phosphorylate multiple downstream targets including H2AX, Chk2, and repair factors. Many viruses have evolved to cope with DNA damage or interfere with host cell DNA-damage response/repair pathways (Martin-Lluesma et al, 2008), thereby affecting host genome stability. At present, it remains unclear whether HBx is involved in the G 2 DNA-damage checkpoint.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

View full text Add to dashboard Cite

Genetic instability is intimately associated with tumour development. In particular, liver cancers associated with hepatitis B virus (HBV) exhibit high genetic instability; however, our understanding of the underlying molecular mechanisms remains limited. In this study, we found that c-H2AX, a marker of DNA double-strand breaks (DSBs), and the levels of phospho-Chk2 (p-Chk2, the activated form) were significantly elevated in HBV-associated hepatocellular carcinomas and neighbouring regenerating nodules. Likewise, introduction of the pHBV or pMyc-HBx plasmids into cells induced accumulation of c-H2AX foci and increased the p-Chk2 level. In these cells, inhibitory phosphorylation of Cdc25C phosphatase (Ser 216 ) and CDK1(Tyr 15 ) was elevated; consequently, cell-cycle progression was delayed at G 2 /M phase, suggesting that activation of the ATM-Chk2 pathway by the HBV X protein (HBx) induces cell-cycle delay. Accordingly, inhibition of ataxia telangiectasia mutated (ATM) by caffeine or siRNA abolished the increase in the p-Chk2 level and restored the delayed CDK1 kinase activity in ChangX cells. We also found that cytoplasmic HBx, but not nuclear HBx, induced reactive oxygen species (ROS) production and led to the accumulation of c-H2AX foci and the increased p-Chk2 level. Together, these data indicate that HBx-induced ROS accumulation induces DNA damage that activates the ATM-Chk2 pathway. Our findings provide insight into the mechanisms of HBV pathogenesis.

show abstract

“…HBx stimulates HBV replication in multiple experimental systems, including cultured primary rat and human hepatocytes, some liver cell lines, livers of normal mice, and chimeric mice with humanized livers (14)(15)(16)(17)(18)(19). HBx is also thought to play an important role in the development of HBV-associated HCC due to the regulatory effects of HBx on cellular signaling pathways, DNA damage repair mechanisms, the cell cycle, and apoptosis (14,(20)(21)(22)(23)(24). Some HBx activities, such as its role in regulating apoptosis, appear to be context dependent and have varied depending upon the model system that was used to assess this HBx activity (8,11,25).…”

mentioning

confidence: 99%

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

113

126

View full text Add to dashboard Cite

Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4␣ (HNF4␣) is a target of HBx-regulated AKT, and we link HNF4␣ to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is Chronic infection with hepatitis B virus (HBV) remains a major global health problem. Despite the availability of effective HBV vaccines, there are ϳ350 million people worldwide who are chronically infected with HBV. Chronic HBV infection is the major cause of the development of hepatocellular carcinoma (HCC) (1). The level of HBV replication in a chronically HBV-infected individual can vary throughout the course of the infection, and the rise and fall of HBV replication during a chronic infection may affect disease progression (2, 3). There are limited therapeutic options for treating a chronic HBV infection, and the emergence of HBV mutants that are resistant to available therapies is common. Moreover, available anti-HBV drugs typically do not completely eliminate HBV in chronically infected individuals due to the presence and stability of covalently closed circular DNA (cccDNA), a replicative intermediate of HBV that is localized to the nucleus of HBV-infected hepatocytes (4-7). Consequently, there is continued interest in understanding the mechanisms that regulate HBV replication and could serve as potential therapeutic targets.HBV is an enveloped, partially double-stranded DNA virus that belongs to the Hepadnaviridae family of viruses (8). Although HBV is a DNA virus, it replicates through reverse transcription of an RNA intermediate. HBV replication occurs within the viral capsid in the cytosol of hepa...

show abstract

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Cited by 96 publications

References 39 publications

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Contact Info

Product

Resources

About