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Aurora B prevents chromosome arm separation defects by promoting telomere dispersion and disjunction.

Reyes C, Serrurier C, Gauthier T, Gachet Y, Tournier S - J. Cell Biol. (2015)

Bottom Line: Dispersion is promoted by the dissociation of Swi6/HP1 and cohesin Rad21 from telomeres, whereas disjunction occurs at anaphase after the phosphorylation of condensin subunit Cnd2.Strikingly, we demonstrate that deletion of Ccq1, a telomeric shelterin component, rescued cell death after Aurora inhibition by promoting the loading of condensin on chromosome arms.Our findings reveal an essential role for telomeres in chromosome arm segregation.

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Affiliation: Laboratoire de biologie cellulaire et moléculaire du contrôle de la prolifération, Université de Toulouse, F-31062 Toulouse, France Centre National de la Recherche Scientifique, LBCMCP-UMR5088, F-31062 Toulouse, France.

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Telomere nondisjunction mechanically disturbs spindle elongation and leads to the formation of anaphase chromatin bridges. (A) Single cell analysis of spindle elongation during mitotic progression in the absence (gray lines, n = 22) or in the presence of 10 µm Napp1 (red, n = 13, and green, n = 4 lines). In the presence of 10 µm Napp1, cells displaying telomere segregation defects and merotelic attachments are shown in red, whereas cells with telomere nondisjunction defects are shown in green. (B) Mean rate of spindle elongation for the different phenotypes shown in A. (C) Example of a fine chromatin bridge seen after Aurora inhibition with correctly segregated kinetochores. (D) Percentage of anaphase chromatin bridges, merotely, and aneuploidy phenotypes in control (n = 206), after Aurora inhibition (n = 293), or in cells deleted for the monopolin subunit Pcs1 (n = 221). Light gray, anaphase bridges; dark gray, merotely; white, aneuploidy. Error bars indicate SD obtained from three independent experiments.
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fig3: Telomere nondisjunction mechanically disturbs spindle elongation and leads to the formation of anaphase chromatin bridges. (A) Single cell analysis of spindle elongation during mitotic progression in the absence (gray lines, n = 22) or in the presence of 10 µm Napp1 (red, n = 13, and green, n = 4 lines). In the presence of 10 µm Napp1, cells displaying telomere segregation defects and merotelic attachments are shown in red, whereas cells with telomere nondisjunction defects are shown in green. (B) Mean rate of spindle elongation for the different phenotypes shown in A. (C) Example of a fine chromatin bridge seen after Aurora inhibition with correctly segregated kinetochores. (D) Percentage of anaphase chromatin bridges, merotely, and aneuploidy phenotypes in control (n = 206), after Aurora inhibition (n = 293), or in cells deleted for the monopolin subunit Pcs1 (n = 221). Light gray, anaphase bridges; dark gray, merotely; white, aneuploidy. Error bars indicate SD obtained from three independent experiments.

Mentions: Aurora B inhibition causes several types of chromosome attachment defects in mitosis, e.g., merotelic attachments (Tanaka et al., 2002; Cimini et al., 2006; Knowlton et al., 2006), which antagonize the spindle elongation rate (Courtheoux et al., 2009). Because merotelic attachments are partly corrected during anaphase B by spindle elongation forces (Courtheoux et al., 2009), it seems unlikely that the lethality of Aurora-inhibited cells arises from this type of defect. We thus analyzed the impact of telomere nondisjunction on spindle elongation. We followed the changes in spindle elongation in single cells (cdc25-22 ark1-as3 synchronised in G2) expressing markers for telomeres (Fig. 3 A, taz1-gfp, green), kinetochores (ndc80-gfp, green), centromeres (mis6-rfp, red), and SPBs (cdc11-cfp, blue). In control cells (Fig. 3, A and B, gray), the spindle elongation rate was 0.87 ± 0.09 µm/min. As expected, inhibition of Aurora B in metaphase led to the appearance of merotelic attachments in anaphase as judged by the appearance of stretched kinetochores (Fig. 3, A and B, red). Concomitantly, the spindle elongation rate was halved (0.39 ± 0.12 µm/min). In cells lacking merotelic attachments it was possible to observe the impact of the nondisjunction of chromosome arms on mitotic progression (Fig. 3, A and B, green). In such cells, DAPI staining revealed the presence of fine chromatin bridges with fully separated kinetochores (Fig. 3 C, note the presence of telomere signals at the cell midzone). The spindle elongation rate was reduced (0.4 ± 0.06 µm/min; Fig. 3, A and B, green) and spindles often collapsed (Fig. S3 A). Eventually, cell death occurred after cell abscission (Fig. S3 B), similarly to the so-called cut phenotype (the formation of the septum between daughter cells in the absence of normal nuclear division; Hirano et al., 1986). Thus, telomere nondisjunction and/or defects in chromosome arm separation can impact mitotic progression independently of merotelic attachment.


Aurora B prevents chromosome arm separation defects by promoting telomere dispersion and disjunction.

Reyes C, Serrurier C, Gauthier T, Gachet Y, Tournier S - J. Cell Biol. (2015)

Telomere nondisjunction mechanically disturbs spindle elongation and leads to the formation of anaphase chromatin bridges. (A) Single cell analysis of spindle elongation during mitotic progression in the absence (gray lines, n = 22) or in the presence of 10 µm Napp1 (red, n = 13, and green, n = 4 lines). In the presence of 10 µm Napp1, cells displaying telomere segregation defects and merotelic attachments are shown in red, whereas cells with telomere nondisjunction defects are shown in green. (B) Mean rate of spindle elongation for the different phenotypes shown in A. (C) Example of a fine chromatin bridge seen after Aurora inhibition with correctly segregated kinetochores. (D) Percentage of anaphase chromatin bridges, merotely, and aneuploidy phenotypes in control (n = 206), after Aurora inhibition (n = 293), or in cells deleted for the monopolin subunit Pcs1 (n = 221). Light gray, anaphase bridges; dark gray, merotely; white, aneuploidy. Error bars indicate SD obtained from three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig3: Telomere nondisjunction mechanically disturbs spindle elongation and leads to the formation of anaphase chromatin bridges. (A) Single cell analysis of spindle elongation during mitotic progression in the absence (gray lines, n = 22) or in the presence of 10 µm Napp1 (red, n = 13, and green, n = 4 lines). In the presence of 10 µm Napp1, cells displaying telomere segregation defects and merotelic attachments are shown in red, whereas cells with telomere nondisjunction defects are shown in green. (B) Mean rate of spindle elongation for the different phenotypes shown in A. (C) Example of a fine chromatin bridge seen after Aurora inhibition with correctly segregated kinetochores. (D) Percentage of anaphase chromatin bridges, merotely, and aneuploidy phenotypes in control (n = 206), after Aurora inhibition (n = 293), or in cells deleted for the monopolin subunit Pcs1 (n = 221). Light gray, anaphase bridges; dark gray, merotely; white, aneuploidy. Error bars indicate SD obtained from three independent experiments.
Mentions: Aurora B inhibition causes several types of chromosome attachment defects in mitosis, e.g., merotelic attachments (Tanaka et al., 2002; Cimini et al., 2006; Knowlton et al., 2006), which antagonize the spindle elongation rate (Courtheoux et al., 2009). Because merotelic attachments are partly corrected during anaphase B by spindle elongation forces (Courtheoux et al., 2009), it seems unlikely that the lethality of Aurora-inhibited cells arises from this type of defect. We thus analyzed the impact of telomere nondisjunction on spindle elongation. We followed the changes in spindle elongation in single cells (cdc25-22 ark1-as3 synchronised in G2) expressing markers for telomeres (Fig. 3 A, taz1-gfp, green), kinetochores (ndc80-gfp, green), centromeres (mis6-rfp, red), and SPBs (cdc11-cfp, blue). In control cells (Fig. 3, A and B, gray), the spindle elongation rate was 0.87 ± 0.09 µm/min. As expected, inhibition of Aurora B in metaphase led to the appearance of merotelic attachments in anaphase as judged by the appearance of stretched kinetochores (Fig. 3, A and B, red). Concomitantly, the spindle elongation rate was halved (0.39 ± 0.12 µm/min). In cells lacking merotelic attachments it was possible to observe the impact of the nondisjunction of chromosome arms on mitotic progression (Fig. 3, A and B, green). In such cells, DAPI staining revealed the presence of fine chromatin bridges with fully separated kinetochores (Fig. 3 C, note the presence of telomere signals at the cell midzone). The spindle elongation rate was reduced (0.4 ± 0.06 µm/min; Fig. 3, A and B, green) and spindles often collapsed (Fig. S3 A). Eventually, cell death occurred after cell abscission (Fig. S3 B), similarly to the so-called cut phenotype (the formation of the septum between daughter cells in the absence of normal nuclear division; Hirano et al., 1986). Thus, telomere nondisjunction and/or defects in chromosome arm separation can impact mitotic progression independently of merotelic attachment.

Bottom Line: Dispersion is promoted by the dissociation of Swi6/HP1 and cohesin Rad21 from telomeres, whereas disjunction occurs at anaphase after the phosphorylation of condensin subunit Cnd2.Strikingly, we demonstrate that deletion of Ccq1, a telomeric shelterin component, rescued cell death after Aurora inhibition by promoting the loading of condensin on chromosome arms.Our findings reveal an essential role for telomeres in chromosome arm segregation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de biologie cellulaire et moléculaire du contrôle de la prolifération, Université de Toulouse, F-31062 Toulouse, France Centre National de la Recherche Scientifique, LBCMCP-UMR5088, F-31062 Toulouse, France.

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Related in: MedlinePlus