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

Sunyoung Chae, Jae Hoon Ji, Soon Hwan Kwon, Ho Soo Lee, Jung Mi Lim, Dongmin Kang, Chang Woo Lee, Hyeseong Cho

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17 Scopus citations


Hepatitis B virus (HBV) X prote in (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 a (HBxAPa)/Rsf-1 associates with hBubR1 and HBx in the chromatin fraction during mitosis. Depletion of HBxAPa/Rsf-1 abolished the interaction between HBx and hBubR1, indicating that HBxAPa/Rsf-1 mediates these interactions. Knockdown of HBxAPa/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 HBxAPa/Rsf-1 were essential for these interactions. Thus, binding of HBx to hBubR1, stabilized by HBxAPa/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 HBxAPa/Rsf-1, providing a novel mechanism for induction of genomic instability by a viral pathogen in hepatocarcinogenesis.

Original languageEnglish
Pages (from-to)1680-1688
Number of pages9
Issue number7
StatePublished - Jul 2013

Bibliographical note

Funding Information:
National Research Foundation of Korea grants funded by the Korea government (MEST) [No. 2012-0009203 (SRC)].


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