Merotelic kinetochore attachment: causes and effects - PubMed (original) (raw)

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Merotelic kinetochore attachment: causes and effects

Juraj Gregan et al. Trends Cell Biol. 2011 Jun.

Abstract

Accurate chromosome segregation depends on the proper attachment of sister kinetochores to microtubules emanating from opposite spindle poles. Merotelic kinetochore orientation is an error in which a single kinetochore is attached to microtubules emanating from both spindle poles. Despite correction mechanisms, merotelically attached kinetochores can persist until anaphase, causing chromatids to lag on the mitotic spindle and hindering their timely segregation. Recent studies showing that merotelic kinetochore attachment represents a major mechanism of aneuploidy in mitotic cells and is the primary mechanism of chromosomal instability in cancer cells have underlined the importance of studying merotely. Here, we highlight recent progress in our understanding of how cells prevent and correct merotelic kinetochore attachments.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Putative microtubule site clamp Pcs1/Mde4 and centromeric heterochromatin are required to prevent merotelic attachments in fission yeast. Lagging chromosomes caused by merotelic attachment frequently occur in fission yeast cells lacking the components of the putative microtubule site clamp Pcs1/Mde4 or cells defective in centromeric heterochromatin [28–30]. The kinetochore proteins Pcs1 and Mde4 have been proposed to clamp together (or crosslink) microtubule-binding sites. Clr4/Swi6-dependent centromeric heterochromatin might provide rigidity to the kinetochore, which is necessary for the proper orientation of microtubule-binding sites. Disturbing either of these systems leads to high frequencies of merotelic attachments.

Figure 2

Figure 2

Model of the Aurora B-mediated correction of merotelic attachments**. (a)** In the absence of tension across sister kinetochores, centromeric Aurora B is in close proximity to, and thereby is able to phosphorylate, its kinetochore substrates. This leads to the destabilization of kinetochore microtubules [41–46]. (b) Upon the establishment of amphitelic attachment, microtubules pull the kinetochore away from the inner centromere and thereby out of reach of Aurora B. Consequently, kinetochore–microtubule attachment is stabilized. (c) Upon merotelic attachment (in this example, merotely occurs because of the absence of putative microtubule site clamp Pcs1/Mde4), the portion of a kinetochore attached to the incorrect pole tends to be stretched toward the inner kinetochore region. This could bring the microtubule attachment sites bound to the incorrect pole within the region of high Aurora B activity, resulting in the selective detachment of the misattached microtubules.

Figure 3

Figure 3

Multipolar spindle geometry promotes merotelic kinetochore attachments. (a) In normal unperturbed mitosis, sister kinetochores are attached amphitelically and segregate to opposite poles of the bipolar spindle during anaphase. (b) CIN cells with supernumerary centrosomes assemble multipolar spindles, which allows for the frequent formation of merotelic attachments. This is followed by the clustering of centrosomes into two poles and division in a bipolar fashion. During anaphase, merotelically attached kinetochores give rise to lagging chromosomes, which might lead to mis-segregation .

Figure I

Figure I

Types of kinetochore attachments during mitosis. Whereas only one of the two sister kinetochores is attached to spindle microtubules in monotelic attachment, sister kinetochores are attached to microtubules emanating from opposite spindle poles in amphitelic attachment. Monotelic kinetochore attachment is an intermediate state preceding proper amphitelic attachment. There are two types of erroneous kinetochore attachments: syntelic attachment, where both sister kinetochores interact with microtubules emanating from the same spindle pole, and merotelic attachment, where a single kinetochore is connected to both spindle poles. There are 15–30 microtubule attachment sites at vertebrate kinetochores, thereby providing considerable opportunity for generating merotelic attachments. Three types of merotelic attachments have been observed: i) balanced merotelic (similar number of kinetochore microtubules attached from both poles), ii) mero-amphitelic (more kinetochore microtubules emanating from the pole opposite to that of the sister kinetochore) and iii) mero-syntelic (more kinetochore microtubules emanating from the pole to which the sister kinetochore is attached) . Chromosomes with monotelic or syntelic attachments are also referred to as mono-oriented, whereas those with amphitelic or merotelic attachments are referred to as bioriented. To segregate chromosomes properly, erroneous kinetochore attachments should be corrected and amphitelic attachments stabilized.

Figure II

Figure II

Merotelically attached kinetochores in PtK1 cells. PtK1 cells are ideal for studying kinetochores because of the small number of chromosomes and the fact that the cells remain flat throughout mitosis, making them amenable for high-resolution light microscopy. The images show live PtK1 cells microinjected with X-rhodamine-labeled tubulin and Alexa 488-labeled CENP-F antibodies to fluorescently label kinetochore fibers (red) and kinetochores/spindle poles (green), respectively. (a) Late prometaphase PtK1 cell with one merotelic kinetochore (arrow) aligned at the metaphase plate. (b) Anaphase PtK1 cell with two merotelically attached lagging chromosomes (arrows).

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