Genome stability is ensured by temporal control of kinetochore-microtubule dynamics

被引：354

作者：

Bakhoum, Samuel F. ^{[1
,2
]}

Thompson, Sarah L. ^{[1
,2
]}

Manning, Amity L. ^{[1
,2
]}

Compton, Duane A. ^{[1
,2
]}

机构：

[1] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA

[2] Norris Cotton Canc Ctr, Lebanon, NH 03766 USA

来源：

NATURE CELL BIOLOGY | 2009年 / 11卷 / 01期

基金：

美国国家卫生研究院;

关键词：

SPINDLE-ASSEMBLY CHECKPOINT; MAMMALIAN TISSUE-CELLS; AURORA-B; CHROMOSOME INSTABILITY; COLORECTAL CANCERS; MITOTIC CENTROMERE; CLONAL EVOLUTION; ERROR-CORRECTION; REGULATES MCAK; MITOSIS;

D O I：

10.1038/ncb1809

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Most solid tumours are aneuploid and many frequently mis-segregate chromosomes. This chromosomal instability is commonly caused by persistent mal-oriented attachment of chromosomes to spindle microtubules. Chromosome segregation requires stable microtubule attachment at kinetochores, yet those attachments must be sufficiently dynamic to permit correction of mal-orientations. How this balance is achieved is unknown, and the permissible boundaries of attachment stability versus dynamics essential for genome stability remain poorly understood. Here we show that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore-microtubule dynamics during distinct phases of mitosis to correct mal-orientations. Few-fold reductions in kinetochore-microtubule turnover, particularly in early mitosis, induce severe chromosome segregation defects. In addition, we show that stimulation of microtubule dynamics at kinetochores restores stability to chromosomally unstable tumour cell lines, establishing a causal relationship between deregulation of kinetochore-microtubule dynamics and chromosomal instability. Thus, temporal control of microtubule attachment to chromosomes during mitosis is central to genome stability in human cells.

引用

页码：27 / U51

页数：14

共 39 条

[1] Aurora B regulates MCAK at the mitotic centromere [J].

Andrews, PD ;

Ovechkina, Y ;

Morrice, N ;

Wagenbach, M ;

Duncan, K ;

Wordeman, L ;

Swedlow, JR .

DEVELOPMENTAL CELL, 2004, 6 (02) :253-268

[2] Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers [J].

Barber, Thomas D. ;

McManus, Kirk ;

Yuen, Karen W. Y. ;

Reis, Marcelo ;

Parmigiani, Giovanni ;

Shen, Dong ;

Barrett, Irene ;

Nouhi, Yasaman ;

Spencer, Forrest ;

Markowitz, Sanford ;

Velculescu, Victor E. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Lengauer, Christoph ;

Hieter, Philip .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (09) :3443-3448

[3] Mutations of mitotic checkpoint genes in human cancers [J].

Cahill, DP ;

Lengauer, C ;

Yu, J ;

Riggins, GJ ;

Willson, JKV ;

Markowitz, SD ;

Kinzler, KW ;

Vogelstein, B .

NATURE, 1998, 392 (6673) :300-303

[4] Molecular architecture of the kinetochore-microtubule interface [J].

Cheeseman, Iain M. ;

Desai, Arshad .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2008, 9 (01) :33-46

[5] Aneuploidy: a matter of bad connections [J].

Cimini, D ;

Degrassi, F .

TRENDS IN CELL BIOLOGY, 2005, 15 (08) :442-451

[6] Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms [J].

Cimini, D ;

Moree, B ;

Canman, JC ;

Salmon, ED .

JOURNAL OF CELL SCIENCE, 2003, 116 (20) :4213-4225

[7] Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells [J].

Cimini, D ;

Tanzarella, C ;

Degrassi, F .

MUTAGENESIS, 1999, 14 (06) :563-568

[8] Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells [J].

Cimini, D ;

Howell, B ;

Maddox, P ;

Khodjakov, A ;

Degrassi, F ;

Salmon, ED .

JOURNAL OF CELL BIOLOGY, 2001, 153 (03) :517-527

[9] Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors [J].

Cimini, Daniela ;

Wan, Xiaohu ;

Hirel, Christophe B. ;

Salmon, E. D. .

CURRENT BIOLOGY, 2006, 16 (17) :1711-1718

[10] Kinetochore microtubule dynamics and attachment stability are regulated by Hec1 [J].

DeLuca, Jennifer G. ;

Gall, Walter E. ;

Ciferri, Claudio ;

Cimini, Daniela ;

Musacchio, Andrea ;

Salmon, E. D. .

CELL, 2006, 127 (05) :969-982

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