Centrosome cycle

Centrosomes are the major microtubule organizing center (MTOC) in mammalian cells. ^[1] Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with aneuploidy. A centrosome is composed of two orthogonal cylindrical proteins, called centrioles, which are surrounded by an electron dense and protein dense amorphous cloud of pericentriolar matrix (PCM). ^[2] The PCM is essential for nucleation and organization of microtubules. ^[2] The centrosome cycle is important to ensure that daughter cells receive a centrosome after cell division. As the cell cycle progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle, so that by the time mitosis occurs there are two centrosomes.

Schematic view of the centrosome cycle in relation to the cell cycle. ^[1]

The centrosome cycle consists of four phases that are synchronized to cell cycle; these include: centrosome duplication (G1/S), centrosome maturation (G2), centrosome separation (M), and centrosome disorientation (M/G1). Centrioles are generated in new daughter cells through duplication of preexisting centrioles in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by PCM as a results of cell division. However, the two centrioles are of different ages. One centriole originated from the mother cell and the other was replicated from the mother centriole during the daughter cell cycle. A procentriole (what will eventually become a daughter centriole) begins to form near each existing mother centriole during the advancement from G1 to S phase in the cell cycle. ^{[3] [4] [5]} It is possible to distinguish between these two centrioles, because the mother and daughter centriole differ morphologically and functionally. ^[6] For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate. During S and G2 phase of the cell cycle, the daughter centrioles are elongating until the reach the length of the mother centriole. When a daughter cell has reached full length, the mother and daughter form a diplosome. A diplosome is a rigid complex formed by an orthogonal mother and daughter centriole that aids in the processes of mitosis. As mitosis occurs, the distance between mother and daughter centriole increases until, congruent with anaphase, the diplosome breakdown and each centriole is surrounded by its own PCM. ^[3]

Centrosome Duplication

Cell Cycle Regulation of Centrosome Duplication

Centrosome duplication is heavily regulated by cell cycle controls. This link between the cell cycle and the centrosome cycle is mediated by cyclin-dependent kinase 2 (Cdk2). There has been ample evidence ^{[7] [8] [9] [10]} that Cdk2 is necessary for both DNA replication and centrosome duplication, which are both key events in S phase. It has also been shown ^{[11] [12] [9]} that Cdk2 complexes with both cyclin A and cyclin E and this complex is critical for centrosome duplication. Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication. These include: nucleophosmin (NPM/B23), CP110, and Msp1. ^[2] Nucleophosmin is only found in unreplicated centrosomes and it’s phosphorylation by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation. ^{[13] [14]} CP110 is an important centrosomal protein that is phosphorylated by both mitotic and interphase Cdk/cyclin complexes and is thought to influence centrosome duplication in S phase. [19] MSP-1 is a protein kinase that is essential to the spindle assembly checkpoint. ^[15]

Centrosome Maturation

Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome. ^[1] This increase in γ -tubulin allows the mature centrosome to have a greater ability to nucleate microtubules. Phosphorylation is a key regulatory role in centrosome maturation and it is thought that Polo-like kinases (Plks) and Aurora kinases are responsible for this phosphorylation. [21] The phosphorylation of downstream targets of Plks and Aurora A lead to the recruitment of γ –tubulin and other proteins that form PCM around the centrioles. [23]

Centrosome Separation

In early mitosis, several motor proteins drive the separation of centrosomes. With the onset of prophase, the motor protein, dynein, provides the majority of the force required to pull the two centrosomes apart. The separation event actually occurs at the G2/M transition and happens in two steps. First, the connection between the two parental centrioles is destroyed. Second, the centrosomes are separated via microtubules motor proteins. ^[1]

Centrosome Disorientation

Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles. ^[1] Once disorientation occurs, the mature centriole begins to move toward the cleave furrow and it was purposed that this movement is a key step in abscission, the terminal phase of cell division. ^[16]

Disregulation of the Centrosome Cycle

Improper progression through the centrosome cycle can lead to incorrect numbers of centrosomes and aneuploidy, which could eventually lead to cancer. The role of centrosomes in tumor progression is unclear. The misexpression of genes such as, p53, BRCA1, Mdm2, Aurora-A and survivin, causes an increase in the amount of centrosomes present in a cell. However, it is not well understood how these genes influence the centrosome or how the increase number of centrosomes influences tumor progression. ^[17]

References

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3. ^ ^{a b} Chrétien, D; Buendia, B, Fuller, SD, Karsenti, E (1997 Nov). "Reconstruction of the centrosome cycle from cryoelectron micrographs". Journal of structural biology 120 (2): 117–33. doi:10.1006/jsbi.1997.3928. PMID 9417977. 
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