title: HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint.
abstract: Accurate chromosomal segregation is monitored by the mitotic checkpoint, and an increased rate of chromosomal missegregation leads to chromosomal instability (CIN). Here, we demonstrate that the HBV X protein (HBx) binds BubR1, a component of the mitotic checkpoint complex and co-localizes with BubR1 at the kinetochores. HBx binding to BubR1 attenuates the association between BubR1 and CDC20, an activator of the anaphase-promoting complex/cyclosome (APC/C) and induces slippage of mitotic arrest in the presence of microtubule poisons. In addition, HBx binding to BubR1 results in the accumulation of lagging chromosomes and chromosome bridges. In contrast, a C-terminally truncated HBx mutant (HBx(1-100)) fails to bind BubR1 and does not cause aberrant chromosomal segregation. This provides a novel mechanism for dysregulation of the mitotic checkpoint by a viral pathogen linking it to the accumulation of chromosomal instability in HBV-associated hepatocarcinogenesis.
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: S-Y
authors.initials: SY
authors.lastname: Park
authors.forename: H
authors.initials: H
authors.lastname: Yong
authors.forename: J K
authors.initials: JK
authors.lastname: Famulski
authors.forename: S
authors.initials: S
authors.lastname: Chae
authors.forename: J-H
authors.initials: JH
authors.lastname: Lee
authors.forename: C-M
authors.initials: CM
authors.lastname: Kang
authors.forename: H
authors.initials: H
authors.lastname: Saya
authors.forename: G K
authors.initials: GK
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Cho
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D018386:Kinetochores; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D008941:Spindle Apparatus; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases