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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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Related in: MedlinePlus

Epigenetic specification of centromeric chromatin. (A) The histone-fold domain of histone H3 proteins is composed of four α-helical domains (αN and α1–α3). Loop 1 separates α1 and α2. The CENP-A targeting domain (CATD) is sufficient for localization to centromeres when substituted into canonical H3 (the amino acids highlighted in orange are required in Drosophila). The CATD was identified for a 10-fold slowing of hydrogen exchange along the peptide backbone, probably because of increase rigidity of the interface it forms with its histone H4 (Black et al, 2004). (B) In non-centromeric regions, canonical histone H3 assembles into octameric nucleosomes composed of two H2A, H2B, H3, and H4 histone subunits. In centromeric chromatin, CENP-A can assemble into homotypic octamers, in which both H3 subunits are replaced by CENP-A, or into heterotypic octamers, which contain one canonical H3 and one CENP-A subunit. In Drosophila melanogaster, CENP-A has been reported to form half nucleosomes, homotypic tetramers containing one subunit each of H2A, H2B, H4, and CENP-A/CID. (C) Ribbond model of the nucleosome core particle (PDB ID 2CV5). Histone H3 is in red. When grafted onto histone H3, the CATD of CENP-A (green) allows specific and selective incorporation of the H3 chimaera at the centromere. The CENP-A2:H42 tetramers are more compact and rigid than the H32:H42 tetramers (Black et al, 2004). (D) CENP-A is only replenished in telophase. Thus, chromatin entering S phase with a full complement of CENP-A, emerges from DNA replication with half the original levels. The halved levels are retained throughout mitosis. (E) The localization pattern of M18BP1, a subunit of the Mis18 complex. The figure derives from Maddox et al (2007). The dots on the right panel represent centromeres/kinetochores.
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f4: Epigenetic specification of centromeric chromatin. (A) The histone-fold domain of histone H3 proteins is composed of four α-helical domains (αN and α1–α3). Loop 1 separates α1 and α2. The CENP-A targeting domain (CATD) is sufficient for localization to centromeres when substituted into canonical H3 (the amino acids highlighted in orange are required in Drosophila). The CATD was identified for a 10-fold slowing of hydrogen exchange along the peptide backbone, probably because of increase rigidity of the interface it forms with its histone H4 (Black et al, 2004). (B) In non-centromeric regions, canonical histone H3 assembles into octameric nucleosomes composed of two H2A, H2B, H3, and H4 histone subunits. In centromeric chromatin, CENP-A can assemble into homotypic octamers, in which both H3 subunits are replaced by CENP-A, or into heterotypic octamers, which contain one canonical H3 and one CENP-A subunit. In Drosophila melanogaster, CENP-A has been reported to form half nucleosomes, homotypic tetramers containing one subunit each of H2A, H2B, H4, and CENP-A/CID. (C) Ribbond model of the nucleosome core particle (PDB ID 2CV5). Histone H3 is in red. When grafted onto histone H3, the CATD of CENP-A (green) allows specific and selective incorporation of the H3 chimaera at the centromere. The CENP-A2:H42 tetramers are more compact and rigid than the H32:H42 tetramers (Black et al, 2004). (D) CENP-A is only replenished in telophase. Thus, chromatin entering S phase with a full complement of CENP-A, emerges from DNA replication with half the original levels. The halved levels are retained throughout mitosis. (E) The localization pattern of M18BP1, a subunit of the Mis18 complex. The figure derives from Maddox et al (2007). The dots on the right panel represent centromeres/kinetochores.

Mentions: The molecular requirements for epigenetic specification of centromeres are the topic of the review by Torras-Llort et al also contained in this focus review series (Torras-Llort et al, 2009). Besides centromere-specific histone modifications (Sullivan and Karpen, 2004; Carroll and Straight, 2006), CENP-A itself may contribute (reviewed in Carroll and Straight, 2006; Black and Bassett, 2008). A 15-residue sequence of CENP-A, the CENP-A targeting domain (CATD), is key for the propagation of centromere identity through successive cell generations (Figure 4A and B) (Black et al, 2004). When grafted onto H3, the CATD is sufficient to specify centromere localization of the H3CATD chimaera (Black et al, 2004). Furthermore, the H3CATD chimaera performs at least some of the functions normally attributed to CENP-A, such as mediating the recruitment of additional kinetochore and SAC components (Black et al, 2007). Although the exact composition of the CENP-A nucleosome remains controversial (Figure 4B) (Dalal et al, 2007; Allshire and Karpen, 2008), CENP-A forms 2:2 tetramers with histone H4 in vitro (Black et al, 2004) (Figure 4C).


The life and miracles of kinetochores.

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

Epigenetic specification of centromeric chromatin. (A) The histone-fold domain of histone H3 proteins is composed of four α-helical domains (αN and α1–α3). Loop 1 separates α1 and α2. The CENP-A targeting domain (CATD) is sufficient for localization to centromeres when substituted into canonical H3 (the amino acids highlighted in orange are required in Drosophila). The CATD was identified for a 10-fold slowing of hydrogen exchange along the peptide backbone, probably because of increase rigidity of the interface it forms with its histone H4 (Black et al, 2004). (B) In non-centromeric regions, canonical histone H3 assembles into octameric nucleosomes composed of two H2A, H2B, H3, and H4 histone subunits. In centromeric chromatin, CENP-A can assemble into homotypic octamers, in which both H3 subunits are replaced by CENP-A, or into heterotypic octamers, which contain one canonical H3 and one CENP-A subunit. In Drosophila melanogaster, CENP-A has been reported to form half nucleosomes, homotypic tetramers containing one subunit each of H2A, H2B, H4, and CENP-A/CID. (C) Ribbond model of the nucleosome core particle (PDB ID 2CV5). Histone H3 is in red. When grafted onto histone H3, the CATD of CENP-A (green) allows specific and selective incorporation of the H3 chimaera at the centromere. The CENP-A2:H42 tetramers are more compact and rigid than the H32:H42 tetramers (Black et al, 2004). (D) CENP-A is only replenished in telophase. Thus, chromatin entering S phase with a full complement of CENP-A, emerges from DNA replication with half the original levels. The halved levels are retained throughout mitosis. (E) The localization pattern of M18BP1, a subunit of the Mis18 complex. The figure derives from Maddox et al (2007). The dots on the right panel represent centromeres/kinetochores.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Epigenetic specification of centromeric chromatin. (A) The histone-fold domain of histone H3 proteins is composed of four α-helical domains (αN and α1–α3). Loop 1 separates α1 and α2. The CENP-A targeting domain (CATD) is sufficient for localization to centromeres when substituted into canonical H3 (the amino acids highlighted in orange are required in Drosophila). The CATD was identified for a 10-fold slowing of hydrogen exchange along the peptide backbone, probably because of increase rigidity of the interface it forms with its histone H4 (Black et al, 2004). (B) In non-centromeric regions, canonical histone H3 assembles into octameric nucleosomes composed of two H2A, H2B, H3, and H4 histone subunits. In centromeric chromatin, CENP-A can assemble into homotypic octamers, in which both H3 subunits are replaced by CENP-A, or into heterotypic octamers, which contain one canonical H3 and one CENP-A subunit. In Drosophila melanogaster, CENP-A has been reported to form half nucleosomes, homotypic tetramers containing one subunit each of H2A, H2B, H4, and CENP-A/CID. (C) Ribbond model of the nucleosome core particle (PDB ID 2CV5). Histone H3 is in red. When grafted onto histone H3, the CATD of CENP-A (green) allows specific and selective incorporation of the H3 chimaera at the centromere. The CENP-A2:H42 tetramers are more compact and rigid than the H32:H42 tetramers (Black et al, 2004). (D) CENP-A is only replenished in telophase. Thus, chromatin entering S phase with a full complement of CENP-A, emerges from DNA replication with half the original levels. The halved levels are retained throughout mitosis. (E) The localization pattern of M18BP1, a subunit of the Mis18 complex. The figure derives from Maddox et al (2007). The dots on the right panel represent centromeres/kinetochores.
Mentions: The molecular requirements for epigenetic specification of centromeres are the topic of the review by Torras-Llort et al also contained in this focus review series (Torras-Llort et al, 2009). Besides centromere-specific histone modifications (Sullivan and Karpen, 2004; Carroll and Straight, 2006), CENP-A itself may contribute (reviewed in Carroll and Straight, 2006; Black and Bassett, 2008). A 15-residue sequence of CENP-A, the CENP-A targeting domain (CATD), is key for the propagation of centromere identity through successive cell generations (Figure 4A and B) (Black et al, 2004). When grafted onto H3, the CATD is sufficient to specify centromere localization of the H3CATD chimaera (Black et al, 2004). Furthermore, the H3CATD chimaera performs at least some of the functions normally attributed to CENP-A, such as mediating the recruitment of additional kinetochore and SAC components (Black et al, 2007). Although the exact composition of the CENP-A nucleosome remains controversial (Figure 4B) (Dalal et al, 2007; Allshire and Karpen, 2008), CENP-A forms 2:2 tetramers with histone H4 in vitro (Black et al, 2004) (Figure 4C).

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