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

Producción científica: Article › revisión exhaustiva

67 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	3457-3464
Número de páginas	8
Publicación	Oncogene
Volumen	27
N.º	24
DOI	https://doi.org/10.1038/sj.onc.1210998
Estado	Published - may 29 2008

Nota bibliográfica

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.

Financiación

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.

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

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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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 - Chae, S.

AU - Lee, J. H.

AU - Kang, C. M.

AU - Saya, H.

AU - Chan, G. K.

AU - Cho, H.

N1 - 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.

PY - 2008/5/29

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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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ER -

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

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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Huella

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