35.8

Attachment of Sister Chromatids

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During mitosis, following the assembly of a bipolar microtubule array, the kinetochore microtubules attach to the sister-chromatids.

Microtubules attach to each chromatid via the kinetochore located at the centromere. Multiple microtubules from the same spindle pole can bind to a single kinetochore to form the kinetochore fiber.

The kinetochore is a multi-layered protein complex. The inner-kinetochore layer secures the kinetochore complex with the sister chromatid. The outer-kinetochore layer includes specialized, rod-shaped, protein complexes called Ndc80 that link microtubules with the kinetochore.

Multiple copies of the Ndc80 complex bind to the plus ends of microtubules. Binding of Ndc80 permits microtubule polymerization and depolymerization to occur at the plus-end while being linked to the kinetochore.

Kinetochores on a sister-chromatid pair attach to microtubules emanating from opposite poles of the mitotic spindle, resulting in the bi-orientation of sister chromatids.

Bi-orientation generates high levels of tension within the kinetochores of sister chromatids. Strong poleward forces exerted by the microtubules pull the kinetochores towards opposite spindle poles. An opposing force resulting from sister-chromatid cohesion resists the poleward force. Tension is used to sense the correct bi-orientation of chromosomes.

A tension-sensing mechanism involves a protein kinase, Aurora B, tethered to the inner-kinetochore layer. During minimal tension or absence of tension, the Aurora B kinase rests in physical proximity to the outer-kinetochore layer, where it can phosphorylate Ndc80 complexes. This phosphorylation reduces the affinity for microtubule binding.

Once the sister chromatids have bioriented, the opposing effects of opposite poleward forces pull the outer-kinetochore layer away from the inner-kinetochore layer, physically distancing and preventing Aurora B kinase from phosphorylating Ndc80 complexes.

Ndc80 proteins, in an unphosphorylated state, strengthen existing microtubule attachment and exhibit increased affinity for additional microtubules. These changes enable microtubules to form stable attachments with the kinetochore.

Successful attachment of sister chromatids to the opposite spindle poles tugs the chromosomes back and forth to assume a position equidistant from the two poles, at the metaphase plate.

Overview

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As cells progress into mitosis, the nuclear envelope breaks down, and the condensed chromosomes are exposed to the array of bipolar microtubules of the mitotic spindle. The kinetochore, a large, disc-shaped protein complex, is present at the centromere region of the sister chromatids and acts as a binding site for the microtubules. Usually, the plus-end of a single microtubule is embedded within the kinetochore. However, some kinetochores first establish lateral contact with the side-wall of a microtubule. Such laterally attached kinetochores move along the microtubule wall with the help of the motor proteins and eventually forming a stable head-on attachment with the plus-end of the microtubule. Initially, chromosomes may have a monotelic attachment, where only one sister kinetochore is attached to a single spindle pole, and the other sister kinetochore remains unattached to microtubules. Subsequently, the unattached sister kinetochore connects with the microtubule from the opposite spindle, resulting in an amphitelic attachment. Amphitelic attachment of the sister chromatids is a prerequisite for accurate segregation of the chromosomes.

The kinetochore-microtubule interaction can also result in incorrect attachments. A syntelic attachment is when both kinetochores of the sister chromatids attach to microtubules from the same spindle pole. A merotelic attachment forms when the microtubules from opposite poles bind to the same kinetochore. Syntelic and merotelic attachments result in chromosomal segregation errors and can be corrected by Aurora-B kinase-dependent mechanisms.

Once a single microtubule has established the correct head-on connection with the kinetochore, additional microtubules from the same spindle can bind to the kinetochore, resulting in the formation of a kinetochore fiber. Such kinetochore fibers can contain 10 to 40 microtubules in animal cells.

The correct microtubule-kinetochore binding generates tension within the kinetochore from opposing forces, where the sister-chromatid cohesive force resists the poleward pull along the microtubules. The kinetochore tension triggers an increase in microtubule-binding affinity, thereby locking the stable attachment in place and ensuring the biorientation of sister chromatids.

Transcript

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$$\rightleftharpoonup{xx}$$ $$\longleftharp{xx}$$, $$\longrightharp{xx}$$,

During mitosis, following the assembly of a bipolar microtubule array, the kinetochore microtubules attach to the sister-chromatids.

Microtubules attach to each chromatid via the kinetochore located at the centromere. Multiple microtubules from the same spindle pole can bind to a single kinetochore to form the kinetochore fiber.

The kinetochore is a multi-layered protein complex. The inner-kinetochore layer secures the kinetochore complex with the sister chromatid. The outer-kinetochore layer includes specialized, rod-shaped, protein complexes called Ndc80 that link microtubules with the kinetochore.

Multiple copies of the Ndc80 complex bind to the plus ends of microtubules. Binding of Ndc80 permits microtubule polymerization and depolymerization to occur at the plus-end while being linked to the kinetochore.

Kinetochores on a sister-chromatid pair attach to microtubules emanating from opposite poles of the mitotic spindle, resulting in the bi-orientation of sister chromatids.

Bi-orientation generates high levels of tension within the kinetochores of sister chromatids. Strong poleward forces exerted by the microtubules pull the kinetochores towards opposite spindle poles. An opposing force resulting from sister-chromatid cohesion resists the poleward force. Tension is used to sense the correct bi-orientation of chromosomes.

A tension-sensing mechanism involves a protein kinase, Aurora B, tethered to the inner-kinetochore layer. During minimal tension or absence of tension, the Aurora B kinase rests in physical proximity to the outer-kinetochore layer, where it can phosphorylate Ndc80 complexes. This phosphorylation reduces the affinity for microtubule binding.

Once the sister chromatids have bioriented, the opposing effects of opposite poleward forces pull the outer-kinetochore layer away from the inner-kinetochore layer, physically distancing and preventing Aurora B kinase from phosphorylating Ndc80 complexes.

Ndc80 proteins, in an unphosphorylated state, strengthen existing microtubule attachment and exhibit increased affinity for additional microtubules. These changes enable microtubules to form stable attachments with the kinetochore.

Successful attachment of sister chromatids to the opposite spindle poles tugs the chromosomes back and forth to assume a position equidistant from the two poles, at the metaphase plate.

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