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The life and miracles of kinetochores.

Santaguida S, Musacchio A - EMBO J. (2009)

Bottom Line: The main functions of kinetochores can be grouped under four modules.The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin.The second module, the outer kinetochore, contributes a microtubule-binding interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

ABSTRACT
Kinetochores are large protein assemblies built on chromosomal loci named centromeres. The main functions of kinetochores can be grouped under four modules. The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin. The second module, the outer kinetochore, contributes a microtubule-binding interface. The third module, the spindle assembly checkpoint, is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. The fourth module discerns correct from improper attachments, preventing the stabilization of the latter and allowing the selective stabilization of the former. In this review, we discuss how the molecular organization of the four modules allows a dynamic integration of kinetochore-microtubule attachment with the prevention of chromosome segregation errors and cell-cycle progression.

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Organization of regional centromeres and kinetochores. (A) The central domain of the centromere of S. pombe possesses a pair of inverted repeat sequence arrays (marked as imr, for innermost repeat). They flank an unconserved central core sequence. Both CENP-A and H3-containing nucleosomes map to the central domain. The central domain is flanked by the cohesin-rich outer domains, consisting of peri-centromeric heterochromatin. In humans, α-satellite DNA is composed of a core of highly ordered 171 bp repeats termed α-I satellite DNA, which is framed on either side by divergent repetitive sequences and retrotransposons, referred to as α-II satellite DNA. At the outskirts, the centromeric chromatin becomes rich in long interspersed element 1 (LINE-1 elements). On normal human chromosomes, the centromere forms on a small subdomain of the α-I satellite DNA, but there are cases in which the centromere forms on DNA devoid of α-satellite repeats. The α-I satellite DNA contains a sequence known as the CENP-B box, which binds in a sequence-specific manner to the CENP-B protein and facilitates, but is not strictly required for, kinetochore formation. The panel was adapted from Allshire and Karpen (2008) (B) Adjacent kinetochores from a metaphase cell obtained by rapid freezing and freeze substitution (reproduced from ref. McEwen et al, 1998). The prominent outer plate (op) structure stains as heavily as chromatin, and is separated from the underlying inner plate (ip) by a well-defined, translucent, middle layer (ml). Bar represents 200 nm. (C) Electron tomography of the outer plate shows a network of crosslinked fibres, 10 nm in diameter and up to 80–90 nm long, of unknown molecular identity. The long fibres aligned in the plane of the outer plate in the absence of microtubules (not shown), but re-oriented as they bound to the side of microtubules (Dong et al, 2007). (D) A scheme for the outer kinetochore of metazoans analogous to that presented in Figure 1B. (E) Average location of kinetochore proteins along the axis of the kinetochore–microtubule attachment in metaphase in D. melanogaster. N- and C- indicated N- and C-termini.
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f2: Organization of regional centromeres and kinetochores. (A) The central domain of the centromere of S. pombe possesses a pair of inverted repeat sequence arrays (marked as imr, for innermost repeat). They flank an unconserved central core sequence. Both CENP-A and H3-containing nucleosomes map to the central domain. The central domain is flanked by the cohesin-rich outer domains, consisting of peri-centromeric heterochromatin. In humans, α-satellite DNA is composed of a core of highly ordered 171 bp repeats termed α-I satellite DNA, which is framed on either side by divergent repetitive sequences and retrotransposons, referred to as α-II satellite DNA. At the outskirts, the centromeric chromatin becomes rich in long interspersed element 1 (LINE-1 elements). On normal human chromosomes, the centromere forms on a small subdomain of the α-I satellite DNA, but there are cases in which the centromere forms on DNA devoid of α-satellite repeats. The α-I satellite DNA contains a sequence known as the CENP-B box, which binds in a sequence-specific manner to the CENP-B protein and facilitates, but is not strictly required for, kinetochore formation. The panel was adapted from Allshire and Karpen (2008) (B) Adjacent kinetochores from a metaphase cell obtained by rapid freezing and freeze substitution (reproduced from ref. McEwen et al, 1998). The prominent outer plate (op) structure stains as heavily as chromatin, and is separated from the underlying inner plate (ip) by a well-defined, translucent, middle layer (ml). Bar represents 200 nm. (C) Electron tomography of the outer plate shows a network of crosslinked fibres, 10 nm in diameter and up to 80–90 nm long, of unknown molecular identity. The long fibres aligned in the plane of the outer plate in the absence of microtubules (not shown), but re-oriented as they bound to the side of microtubules (Dong et al, 2007). (D) A scheme for the outer kinetochore of metazoans analogous to that presented in Figure 1B. (E) Average location of kinetochore proteins along the axis of the kinetochore–microtubule attachment in metaphase in D. melanogaster. N- and C- indicated N- and C-termini.

Mentions: The simplest kinetochores, Saccharomyces cerevisiae's, bind a single microtubule (reviewed in McAinsh et al, 2003; Westermann et al, 2007). They contain approximately 60 proteins, almost 40 of which are clustered in seven different complexes, the CBF3, Ndc80, Mtw1, Spc105, Ctf19, Dam1, and Ipl1 complexes (Figure 1; Supplementary Table I) (McAinsh et al, 2003; Westermann et al, 2007). With few exceptions (most notably the CBF3 and Dam1 complexes), these complexes are conserved from yeast to humans (Figure 2) (Musacchio and Salmon, 2007; Cheeseman and Desai, 2008; Welburn and Cheeseman, 2008).


The life and miracles of kinetochores.

Santaguida S, Musacchio A - EMBO J. (2009)

Organization of regional centromeres and kinetochores. (A) The central domain of the centromere of S. pombe possesses a pair of inverted repeat sequence arrays (marked as imr, for innermost repeat). They flank an unconserved central core sequence. Both CENP-A and H3-containing nucleosomes map to the central domain. The central domain is flanked by the cohesin-rich outer domains, consisting of peri-centromeric heterochromatin. In humans, α-satellite DNA is composed of a core of highly ordered 171 bp repeats termed α-I satellite DNA, which is framed on either side by divergent repetitive sequences and retrotransposons, referred to as α-II satellite DNA. At the outskirts, the centromeric chromatin becomes rich in long interspersed element 1 (LINE-1 elements). On normal human chromosomes, the centromere forms on a small subdomain of the α-I satellite DNA, but there are cases in which the centromere forms on DNA devoid of α-satellite repeats. The α-I satellite DNA contains a sequence known as the CENP-B box, which binds in a sequence-specific manner to the CENP-B protein and facilitates, but is not strictly required for, kinetochore formation. The panel was adapted from Allshire and Karpen (2008) (B) Adjacent kinetochores from a metaphase cell obtained by rapid freezing and freeze substitution (reproduced from ref. McEwen et al, 1998). The prominent outer plate (op) structure stains as heavily as chromatin, and is separated from the underlying inner plate (ip) by a well-defined, translucent, middle layer (ml). Bar represents 200 nm. (C) Electron tomography of the outer plate shows a network of crosslinked fibres, 10 nm in diameter and up to 80–90 nm long, of unknown molecular identity. The long fibres aligned in the plane of the outer plate in the absence of microtubules (not shown), but re-oriented as they bound to the side of microtubules (Dong et al, 2007). (D) A scheme for the outer kinetochore of metazoans analogous to that presented in Figure 1B. (E) Average location of kinetochore proteins along the axis of the kinetochore–microtubule attachment in metaphase in D. melanogaster. N- and C- indicated N- and C-termini.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722247&req=5

f2: Organization of regional centromeres and kinetochores. (A) The central domain of the centromere of S. pombe possesses a pair of inverted repeat sequence arrays (marked as imr, for innermost repeat). They flank an unconserved central core sequence. Both CENP-A and H3-containing nucleosomes map to the central domain. The central domain is flanked by the cohesin-rich outer domains, consisting of peri-centromeric heterochromatin. In humans, α-satellite DNA is composed of a core of highly ordered 171 bp repeats termed α-I satellite DNA, which is framed on either side by divergent repetitive sequences and retrotransposons, referred to as α-II satellite DNA. At the outskirts, the centromeric chromatin becomes rich in long interspersed element 1 (LINE-1 elements). On normal human chromosomes, the centromere forms on a small subdomain of the α-I satellite DNA, but there are cases in which the centromere forms on DNA devoid of α-satellite repeats. The α-I satellite DNA contains a sequence known as the CENP-B box, which binds in a sequence-specific manner to the CENP-B protein and facilitates, but is not strictly required for, kinetochore formation. The panel was adapted from Allshire and Karpen (2008) (B) Adjacent kinetochores from a metaphase cell obtained by rapid freezing and freeze substitution (reproduced from ref. McEwen et al, 1998). The prominent outer plate (op) structure stains as heavily as chromatin, and is separated from the underlying inner plate (ip) by a well-defined, translucent, middle layer (ml). Bar represents 200 nm. (C) Electron tomography of the outer plate shows a network of crosslinked fibres, 10 nm in diameter and up to 80–90 nm long, of unknown molecular identity. The long fibres aligned in the plane of the outer plate in the absence of microtubules (not shown), but re-oriented as they bound to the side of microtubules (Dong et al, 2007). (D) A scheme for the outer kinetochore of metazoans analogous to that presented in Figure 1B. (E) Average location of kinetochore proteins along the axis of the kinetochore–microtubule attachment in metaphase in D. melanogaster. N- and C- indicated N- and C-termini.
Mentions: The simplest kinetochores, Saccharomyces cerevisiae's, bind a single microtubule (reviewed in McAinsh et al, 2003; Westermann et al, 2007). They contain approximately 60 proteins, almost 40 of which are clustered in seven different complexes, the CBF3, Ndc80, Mtw1, Spc105, Ctf19, Dam1, and Ipl1 complexes (Figure 1; Supplementary Table I) (McAinsh et al, 2003; Westermann et al, 2007). With few exceptions (most notably the CBF3 and Dam1 complexes), these complexes are conserved from yeast to humans (Figure 2) (Musacchio and Salmon, 2007; Cheeseman and Desai, 2008; Welburn and Cheeseman, 2008).

Bottom Line: The main functions of kinetochores can be grouped under four modules.The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin.The second module, the outer kinetochore, contributes a microtubule-binding interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

ABSTRACT
Kinetochores are large protein assemblies built on chromosomal loci named centromeres. The main functions of kinetochores can be grouped under four modules. The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin. The second module, the outer kinetochore, contributes a microtubule-binding interface. The third module, the spindle assembly checkpoint, is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. The fourth module discerns correct from improper attachments, preventing the stabilization of the latter and allowing the selective stabilization of the former. In this review, we discuss how the molecular organization of the four modules allows a dynamic integration of kinetochore-microtubule attachment with the prevention of chromosome segregation errors and cell-cycle progression.

Show MeSH
Related in: MedlinePlus