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HBxAPα/Rsf-1-mediated HBx-hBubR1 interactions regulate the mitotic spindle checkpoint and chromosome instability.

Authors
Chae, S; Ji, JH; Kwon, SH; Lee, HS; Lim, JM; Kang, D; Lee, CW; Cho, H
Citation
Carcinogenesis, 34(7):1680-1688, 2013
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
Hepatitis B virus (HBV) X protein (HBx), encoded by the HBV genome, is involved in the development of HBV-mediated liver cancer, whose frequency is highly correlated with chromosomal instability (CIN). We reported previously that HBx induces mitotic checkpoint dysfunction by targeting the human serine/threonine kinase BubR1 (hBubR1). However, the underlying mechanism remained unresolved. Here, we show that HBx protein-associated protein α (HBxAPα)/Rsf-1 associates with hBubR1 and HBx in the chromatin fraction during mitosis. Depletion of HBxAPα/Rsf-1 abolished the interaction between HBx and hBubR1, indicating that HBxAPα/Rsf-1 mediates these interactions. Knockdown of HBxAPα/Rsf-1 with small interfering RNA did not affect the recruitment of hBubR1 to kinetochores; however, it did significantly impair HBx targeting to kinetochores. A deletion mutant analysis revealed that two Kunitz domains of HBx, the Cdc20-binding domain of hBubR1 and full-length of HBxAPα/Rsf-1 were essential for these interactions. Thus, binding of HBx to hBubR1, stabilized by HBxAPα/Rsf-1, significantly attenuated hBubR1 binding to Cdc20 and consequently increased the rate of mitotic aberrations. Collectively, our data show that the HBx impairs hBubR1 function and induces CIN through HBxAPα/Rsf-1, providing a novel mechanism for induction of genomic instability by a viral pathogen in hepatocarcinogenesis.
MeSH terms
Cdc20 ProteinsCell Cycle Proteins/genetics/metabolism*Chromosomal InstabilityHEK293 CellsHeLa CellsHumansKinetochores/metabolismLiver Neoplasms/metabolism/*pathology*M Phase Cell Cycle CheckpointsNuclear Proteins/genetics/*metabolismProtein BindingProtein Interaction MappingProtein Structure, TertiaryProtein-Serine-Threonine Kinases/genetics/*metabolismRNA, Small Interfering/genetics/metabolismSequence DeletionTrans-Activators/genetics/*metabolismTransfection
DOI
10.1093/carcin/bgt105
PMID
23536579
Appears in Collections:
Journal Papers > Research Organization > Genomic Instability Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
지, 재훈조, 혜성
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