Жасуша бөлінісінде хромосомаларға микротүтікшелердің қосылуын қамтамасыз ететін ақуыз кешені

Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore (/k//ᵻ/'/n//ɛ//t//ə//k//ɔər/, / /'/n//iː//t//ə//k//ɔər/) is a disc shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore (= movement place) has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932. Monocentric organisms, including vertebrates, fungi, and most plants, have a single centromeric region on each chromosome which assembles a single, localized kinetochore. Holocentric organisms, such as nematodes and some plants, assemble a kinetochore along the entire length of a chromosome. Kinetochores start, control, and supervise the striking movements of chromosomes during cell division. During mitosis, which occurs after the amount of DNA is doubled in each chromosome (while maintaining the same number of chromosomes) in S phase, two sister chromatids are held together by a centromere. Each chromatid has its own kinetochore, which face in opposite directions and attach to opposite poles of the mitotic spindle apparatus. Following the transition from metaphase to anaphase, the sister chromatids separate from each other, and the individual kinetochores on each chromatid drive their movement to the spindle poles that will define the two new daughter cells. The kinetochore is therefore essential for the chromosome segregation that is classically associated with mitosis and meiosis.

The number of microtubules attached to one kinetochore is variable: in Saccharomyces cerevisiae only one MT binds each kinetochore, whereas in mammals there can be 15–35 MTs bound to each kinetochore. However, not all the MTs in the spindle attach to one kinetochore. There are MTs that extend from one centrosome to the other (and they are responsible for spindle length) and some shorter ones are interdigitated between the long MTs. Professor B. Nicklas (Duke University), showed that, if one breaks down the MT kinetochore attachment using a laser beam, chromatids can no longer move, leading to an abnormal chromosome distribution. These experiments also showed that kinetochores have polarity, and that kinetochore attachment to MTs emanating from one or the other centrosome will depend on its orientation. This specificity guarantees that only one chromatid will move to each spindle side, thus ensuring the correct distribution of the genetic material. Thus, one of the basic functions of the kinetochore is the MT attachment to the spindle, which is essential to correctly segregate sister chromatids. If anchoring is incorrect, errors may ensue, generating aneuploidy, with catastrophic consequences for the cell. To prevent this from happening, there are mechanisms of error detection and correction (as the spindle assembly checkpoint), whose components reside also on the kinetochores. The movement of one chromatid towards the centrosome is produced primarily by MT depolymerization in the binding site with the kinetochore. These movements require also force generation, involving molecular motors likewise located on the kinetochores.

MTs associated to kinetochores present special features: compared to free MTs, kMTs are much more resistant to cold induced depolymerization, high hydrostatic pressures or calcium exposure. Furthermore, kMTs are recycled much more slowly than astral MTs and spindle MTs with free (+) ends, and if kMTs are released from kinetochores using a laser beam, they rapidly depolymerize. In Saccharomyces cerevisiae, the Ndc80 complex has four components: Ndc80p, Nuf2p, Spc24p and Spc25p. Mutants lacking any of the components of this complex show loss of the kinetochore microtubule connection, although kinetochore structure is not completely lost.) are deficient both in the connection to microtubules and in the ability to activate the spindle checkpoint, probably because kinetochores work as a platform in which the components of the response are assembled. The Ndc80 complex is highly conserved and it has been identified in S. pombe, C. elegans, Xenopus, chicken and humans. Studies on Hec1 (highly expressed in cancer cells 1), the human homolog of Ndc80p, show that it is important for correct chromosome congression and mitotic progression, and that it interacts with components of the cohesin and condensin complexes. Different laboratories have shown that the Ndc80 complex is essential for stabilization of the kinetochore microtubule anchoring, required to support the centromeric tension implicated in the establishment of the correct chromosome congression in high eukaryotes. However, formation of robust kinetochore microtubule interactions may also require the function of additional proteins. In yeast, this connection requires the presence of the complex Dam1 DASH DDD. Some members of this complex bind directly to MTs, whereas some others bind to the Ndc80 complex. This means that the complex Dam1 DASH DDD might be an essential adapter between kinetochores and microtubules. However, in animals an equivalent complex has not been identified, and this question remains under intense investigation.

Most chromosome movements in relation to spindle poles are associated to lengthening and shortening of kMTs. One of the features of kinetochores is their capacity to modify the state of their associated kMTs (around 20) from a depolymerization state at their (+) end to polymerization state. This allows the kinetochores from cells at prometaphase to show "directional instability", changing between persistent phases of movement towards the pole (poleward) or inversed (anti poleward), which are coupled with alternating states of kMTs depolymerization and polymerization, respectively. This kinetochore bi stability seem to be part of a mechanism to align the chromosomes at the equator of the spindle without losing the mechanic connection between kinetochores and spindle poles. It is thought that kinetochore bi stability is based upon the dynamic instability of the kMTs (+) end, and it is partially controlled by the tension present at the kinetochore. In mammalian cultured cells, a low tension at kinetochores promotes change towards kMTs depolymerization, and high tension promotes change towards kMTs polymerization. Kinetochore proteins and proteins binding to MTs (+) end (collectively called +TIPs) regulate kinetochore movement through the kMTs (+) end dynamics regulation. However, the kinetochore microtubule interface is highly dynamic, and some of these proteins seem to be bona fide components of both structures. Two groups of proteins seem to be particularly important: kinesins which work like depolymerases, such as KinI kinesins; and proteins bound to MT (+) ends, +TIPs, promoting polymerization, perhaps antagonizing the depolymerases effect. KinI kinesins are named "I" because they present an internal motor domain, which uses ATP to promote depolymerization of tubulin polymer, the microtubule. In vertebrates, the most important KinI kinesin controlling the dynamics of the (+) end assembly is MCAK. However, it seems that there are other kinesins implicated. There are two groups of +TIPs with kinetochore functions. The first one includes the protein adenomatous polyposis coli (APC) and the associated protein EB1, which need MTs to localize on the kinetochores. Both proteins are required for correct chromosome segregation. EB1 binds only to MTs in polymerizing state, suggesting that it promotes kMTs stabilization during this phase. The second group of +TIPs includes proteins which can localize on kinetochores even in absence of MTs. In this group there are two proteins that have been widely studied: CLIP 170 and their associated proteins CLASPs (CLIP associated proteins). CLIP 170 role at kinetochores is unknown, but the expression of a dominant negative mutant produces a prometaphase delay, suggesting that it has an active role in chromosome alignment. CLASPs proteins are required for chromosome alignment and maintenance of a bipolar spindle in Drosophila, humans and yeast.