HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

S. Kim; S. Y. Park; H. Yong; J. K. Famulski; S. Chae; J. H. Lee; C. M. Kang; H. Saya; G. K. Chan; H. Cho

doi:10.1038/sj.onc.1210998

HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

S. Kim, S. Y. Park, H. Yong, J. K. Famulski, S. Chae, J. H. Lee, C. M. Kang, H. Saya, G. K. Chan, H. Cho

Biology

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

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.

Original language	English
Pages (from-to)	3457-3464
Number of pages	8
Journal	Oncogene
Volume	27
Issue number	24
DOIs	https://doi.org/10.1038/sj.onc.1210998
State	Published - May 29 2008

Bibliographical note

Funding Information:
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 Found ation (R13-2003-019). GKC is supported by the Canad ian 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.

Funding

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 Found ation (R13-2003-019). GKC is supported by the Canad ian 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.

Funders	Funder number
Canad ian Institute of Health Research	MOP 57723
Alberta Cancer Board
Canada Foundation for Innovation
Ministry of Education China
Alberta Heritage Foundation for Medical Research
Korean Ministry of Health and Welfare	0320010-2
Korea Science and Engineering Foundation	R13-2003-019
Alberta Science and Research Authority

Keywords

BubR1
Chromosome instability
HBV X
Mitotic checkpoint

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.onc.1210998

Cite this

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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 (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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note = "Funding Information: 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 Found ation (R13-2003-019). GKC is supported by the Canad ian 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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AU - Lee, J. H.

AU - Kang, C. M.

AU - Saya, H.

AU - Chan, G. K.

AU - Cho, H.

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N2 - 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.

AB - 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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HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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