The kinetochore is a proteinaceous structure which forms on centromeres and serves as a spindle fiber attachment site used to pull chromosomes apart and to opposite poles of the nucleus during cell division. Every chromatid has its own kinetochore, thus after the duplication of genetic material each chromosome contains two kinetochores, one on each chromatid. During mitosis, the two kinetochores on each chromosome face in opposite directions so that spindle fibers from each pole attach to separate chromatids. This is known as amphitelic attachment. The kinetochore works as a sensing mechanism, ensuring that the chromosomes are appropriately amphitelically attached. It does this by detecting the tension produced from the counteracting pull from each spindle into the bidirectionally oriented sister kinetochores. Only when this tension is sensed does the cell proceed through the spindle assembly checkpoint (SAC) and begin anaphase.
This process is more complicated in meiosis, as the cell must undergo two subsequent rounds of chromosome segregation without intervening DNA duplication. This is accomplished by a different orientation of the kinetochores in meiosis I through the use of REC8, monopolin proteins, and Aurora B Kinase [58
]. In meiosis I, sister kinetochores are oriented on the same side of the chromosome (monooriented) and attach to spindle fibers in a syntelic fashion to ensure that sister chromatids are pulled towards the same pole of the dividing cell. The tension necessary to proceed through the checkpoint is created by the crossovers between homologous chromosomes, which are pulled in opposite directions. Resolution of the chiasma allows for separation of the joined homologous pairs in anaphase I. Meiosis II then proceeds similarly to mitosis.
Many of the details on kinetochore orientation and rotation in meiosis II have yet to be determined. REC8 is critical for mono-orientation [55
]. Condensins, proteins which play a major role in chromosome condensation and DSB repair during prophase I, are also known to play a role [66
]. Brito et al. showed that in the absence of condensins, a portion of kinetochores biorient during meiosis I [66
]. A third group of proteins called monopolins also play a key role [67
]. Monopolins are meiosis specific proteins [69
]. Through their interaction with Aurora B Kinase, monopolins help ensure that homologs are pulled towards opposite poles of the cell [67
]. Although REC8 plays a clear role in maintaining monooriented sister kinetochores, monopolins alone are able to hold together sister kinetochores independently [67
Another critical part of this process is the spindle apparatus. In the female oocyte, the centrosome is destroyed before meiosis and the cell undergoes an acentrosomal spindle assembly [70
]. The spindle network is instead formed through the action of over 80 self-organized microtubule organized centers (MTOCs) that develop from the cytoplasmic microtubule complex and eventually aggregate into a bipolar network [70
]. Very little is understood about acentrosomal spindle assembly and the differences between the mitotic and meiotic spindle, and further studies are needed.
During meiosis I, mechanisms exist to allow the unique process of homolog separation. Studies have shown that some SAC proteins specifically interact with REC8 and Shugoshin (SGO1 and 2) [56
]. BUB1 is one of the SAC proteins shown to be specifically involved with this process. BUB1 is required for the localization of the meiosis cohesion regulators SGO1 and SGO2 to protect REC8 during meiosis I [72
]. For this reason, BUB1 is thought to be essential for establishing proper kinetochore function [56
]. BUB1 mutation results in chromosome fragmentation and missegregation in Drosophila [56
] and female specific germ cell aneuploidy in mice [56
BUB1 has been noted to be abnormally expressed in several cancers including gastric, colon, esophageal, breast, and melanoma [76
]. The aberrant expression of BUB1 seems to have an especially strong correlation with melanoma [80
]. Lewis et al. used qtPCR to identify molecular expression patterns in melanoma, benign nevi, and lymph nodes [80
]. Of the 20 melanoma-related genes tested, BUB1 was one of the three genes found to have the highest discriminatory potential for distinguishing melanoma, benign nevi, and lymph nodes [80
There is a delicate interplay between kinetochores, the spindle apparatus, and the SAC which, when not functioning properly, would be expected to result in chromosomal segregation abnormalities.