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The hepatitis B virus encoded HBx protein and its interaction with host cell protein DDB1: Implications for viral infection and the pathogenesis of liver cancer

English title The hepatitis B virus encoded HBx protein and its interaction with host cell protein DDB1: Implications for viral infection and the pathogenesis of liver cancer
Applicant Strubin Michel
Number 112496
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.09.2006 - 30.09.2009
Approved amount 335'000.00
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All Disciplines (3)

Discipline
Molecular Biology
Cellular Biology, Cytology
Genetics

Keywords (6)

hepatitis B virus; liver cancer; protein X (HBx); DDB1; cullin-4A; cell growth

Lay Summary (English)

Lead
Lay summary
Chronic infection by hepatitis B virus (HBV) affects more than 350 million people worldwide and is a major causative agent of liver diseases, including cirrhosis and hepatocellular carcinoma, one of the most common cancers in humans. Because current treatments of chronic HBV infection have limited success due to side effects and emergence of drug resistant variants, the development of alternative therapeutic strategies remains a major goal. HBV encodes a small regulatory protein, known as HBx, which is essential for viral infection and has been implicated in HBV-mediated liver oncogenesis. The basis for HBx function in either process remains elusive and is the focus of our research studies. Two among the many activities ascribed to HBx that may be relevant to HBV infection and associated liver cancer are its abilities to promote HBV replication and to induce genetic instability in cultured cells. We obtained structural, biochemical and genetic evidence that both of these activities require interaction of HBx with host cell protein DDB1, an essential subunit of an E3 ligase involved in cell cycle regulation. We further obtained indications that HBx functions by subverting the normal function of the DDB1-containing E3 ligase to target cellular proteins for ubiquitination and subsequent degradation. Our current work is aimed at identifying the cellular targets of HBx and further exploring the role of HBx binding to DDB1 and other cellular proteins under experimental conditions closer to natural HBV infection. Given the likely fundamental importance of the interaction of HBx and DDB1 for natural HBV infection and associated liver cancer, this virus-host protein interaction may represent a promising new target for therapeutic intervention.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Histone chaperone spt16 promotes redeposition of the original h3-h4 histones evicted by elongating RNA polymerase.
Jamai Adil, Puglisi Andrea, Strubin Michel (2009), Histone chaperone spt16 promotes redeposition of the original h3-h4 histones evicted by elongating RNA polymerase., in Molecular cell, 35(3), 377-83.
Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1.
Martin-Lluesma Silvia, Schaeffer Céline, Robert Eva Isabelle, van Breugel Pieter Cornelis, Leupin Olivier, Hantz Olivier, Strubin Michel (2008), Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1., in Hepatology (Baltimore, Md.), 48(5), 1467-76.
Continuous histone H2B and transcription-dependent histone H3 exchange in yeast cells outside of replication.
Jamai Adil, Imoberdorf Rachel Maria, Strubin Michel (2007), Continuous histone H2B and transcription-dependent histone H3 exchange in yeast cells outside of replication., in Molecular cell, 25(3), 345-55.

Associated projects

Number Title Start Funding scheme
100785 1. Mechanisms of transcription activation in vivo 2. Analysis of the interaction between hepatitis B virus encoded X protein and host cell protein DDB1. 01.06.2003 Project funding (Div. I-III)
127384 Part I: Dynamics of Histone Exchange and Epigenetic Modifications during Transcription in vivo Part II: Hijacking of the DDB1 Ubiquitin Ligase by the HBV X Protein: What Role during Infection and Associated Liver Cancer? 01.10.2009 Project funding (Div. I-III)
127384 Part I: Dynamics of Histone Exchange and Epigenetic Modifications during Transcription in vivo Part II: Hijacking of the DDB1 Ubiquitin Ligase by the HBV X Protein: What Role during Infection and Associated Liver Cancer? 01.10.2009 Project funding (Div. I-III)

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