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 (HBx1–100) 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.
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Acknowledgements
This work is supported by grants of the National R&D Program for Cancer Control, Ministry of Health and Welfare (0320010-2) and Korea Science and Engineering Foundation (R13-2003-019). GKC is supported by the Canadian Institute of Health Research (CIHR) MOP 57723, the Alberta Cancer Board, the Alberta Heritage Fund for Medical Research, the Canadian Foundation for Innovation and the Alberta Science and Research Authority. Salary of GKC is supported by a CIHR New Investigator Award. Stipend of JKF is supported by a CIHR Canadian Graduate Scholarships and a Graduate Studentship from the Alberta Cancer Board. S Kim, S Park and S Chae are supported by the BK21 program, Korean Ministry of Education. We thank Dr Dawn Macdonald for proofreading the manuscript.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Kim, S., Park, SY., Yong, H. et al. HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint. Oncogene 27, 3457–3464 (2008). https://doi.org/10.1038/sj.onc.1210998
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DOI: https://doi.org/10.1038/sj.onc.1210998
