Sunyoung Chae, Jae-Hoon Ji, Soon-Hwan Kwon, Ho-Soo Lee, Jung Mi Lim, Dongmin Kang, Chang-Woo Lee, Hyeseong Cho
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine and the Graduate School of Molecular Science and Technology, Ajou University, Suwon, South Korea.
Carcinogenesis 2013 JulHepatitis 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.
Sunyoung Chae, Jae-Hoon Ji, Soon-Hwan Kwon, Ho-Soo Lee, Jung Mi Lim, Dongmin Kang, Chang-Woo Lee, Hyeseong Cho. HBxAPα/Rsf-1-mediated HBx-hBubR1 interactions regulate the mitotic spindle checkpoint and chromosome instability. Carcinogenesis. 2013 Jul;34(7):1680-8
PMID: 23536579
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