Centrosome cycle

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Diagram of the centrosome cycle. Centrosome Cycle.svg
Diagram of the centrosome cycle.

Centrosomes are the major microtubule organizing centers (MTOC) in mammalian cells. [2] Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with aneuploidy. A centrosome is composed of two orthogonal cylindrical protein assemblies, called centrioles, which are surrounded by a protein dense amorphous cloud of pericentriolar material (PCM). [3] The PCM is essential for nucleation and organization of microtubules. [3] 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 in order to have two centrosomes by the time mitosis occurs.

Contents

Since the centrosome organizes the microtubules of a cell, it has to do with the formation of the mitotic spindle, polarity and, therefore, cell shape, as well as all other processes having to do with the mitotic spindle. [2] The centriole is the inner core of the centrosome, and its conformation is typically somewhat like that of spokes on a wheel. It has a somewhat different conformation amount different organisms, but its overall structure is similar. Plants, on the other hand, do not typically have centrioles. [4]

The centrosome cycle consists of four phases that are synchronized to the cell cycle. These include: centrosome duplication during the G1 phase and S Phase, centrosome maturation in the G2 phase, centrosome separation in the mitotic phase, and centrosome disorientation in the late mitotic phase—G1 phase.

Centriole synthesis

Centrioles are generated in new daughter cells through duplication of pre-existing centrioles in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by pericentriolar material as a result of cell division. However, the two centrioles are of different ages. This is because one centriole originates from the mother cell while the other is replicated from the mother centriole during the cell cycle. It is possible to distinguish between the two preexisting centrioles because the mother and daughter centriole differ in both shape and function. [5] For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate.

First, procentrioles begin to form near each preexisting centriole as the cell moves from the G1 phase to the S phase. [6] [7] [8] During S and G2 phases of the cell cycle, the procentrioles elongate until they reach the length of the older mother and daughter centrioles. At this point, the daughter centriole which takes on characteristics of a mother centriole. Once they reach full length, the new centriole and its mother centriole form a diplosome. A diplosome is a rigid complex formed by an orthogonal mother and newly formed centriole (now a 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 breaks down and each centriole is surrounded by its own pericentriolar material. [6]

Centrosome duplication

Cell cycle regulation of centrosome duplication

Centrosomes are only supposed to replicate once in each cell cycle and are therefore highly regulated. [9] The centrosome cycle has been found to be regulated by multiple things, including reversible phosphorylation and proteolysis. [2] It also undergoes specific processes in each step of cell division due to the heavy regulation, which is why the process is so efficient. [9]

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). Cdk2 is a protein kinase (an enzyme) known to regulate the cell cycle. [10] There has been ample evidence [11] [12] [13] [14] that Cdk2 is necessary for both DNA replication and centrosome duplication, which are both key events in S phase. It has also been shown [13] [15] [16] that Cdk2 complexes with both cyclin A and cyclin E and this complex is critical for centrosome duplication. [10] Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication: nucleophosmin (NPM/B23), CP110, and MPS1. [3] Nucleophosmin is only found in unreplicated centrosomes and its phosphorylation by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation. [17] [18] 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 the S phase. [19] MPS1 is a protein kinase that is essential to the spindle assembly checkpoint, [19] and it is thought to possibly remodel an SAS6-cored intermediate between severed mother and daughter centrioles into a pair of cartwheel protein complexes onto which procentrioles assemble. [20]

Centrosome maturation

Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome. [2] This increase in γ -tubulin gives the mature centrosome greater ability to nucleate microtubules. Phosphorylation plays 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. In the first step, the connection between the two parental centrioles is destroyed. In the second step, the centrosomes are separated via microtubule motor proteins. [2]

Centrosome disorientation

Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles. [2] Once disorientation occurs, the mature centriole begins to move toward the cleave furrow. It has been proposed that this movement is a key step in abscission, the terminal phase of cell division. [21]

Centrosome reduction

Centrosome reduction is the gradual loss of centrosomal components that takes place after mitosis and during differentiation [22] In cycling cells, after mitosis the centrosome has lost most of its pericentriolar material (PCM) and its microtubule nucleation capacity. In sperm, centriole structure is also changed in addition to the loss of PCM and its microtubule nucleation capacity. [23]

Dysregulation 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 mis-expression 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 an increase in centrosomes influences tumor progression. [24]

The Centrosome Cycle and Disease

Issues with the centrosome can have detrimental effects on the cell, which can lead to diseases in the organisms hosting the cells. Cancer is a heavily studied disease that has been found to have a relation to the cell's centrosome. [2] Dwarfism, microcephaly, and ciliopathies have also recently been genetically linked to centrosome proteins. [25]

Centrosomes are believed to be related to cancer due to the fact that they contain tumor suppressor proteins and oncogenes. These proteins have been found to cause detrimental alterations in the centrosome of various tumor cells. [26] There are two main categories of the centrosome alteration: structural and functional. The structural changes can lead to different shapes, sizes, numbers, positions, or composition, while the functional changes can lead to issues with the microtubules and mitotic spindles, therefore becoming detrimental in cell division. [26] Researchers are hopeful that the targeting of carious centrosomal proteins may be a possible treatment to or prevention of cancer. [26]

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Centrosome</span> Cell organelle in animal cell helping in cell division

In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progression. The centrosome provides structure for the cell. The centrosome is thought to have evolved only in the metazoan lineage of eukaryotic cells. Fungi and plants lack centrosomes and therefore use other structures to organize their microtubules. Although the centrosome has a key role in efficient mitosis in animal cells, it is not essential in certain fly and flatworm species.

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Telophase</span> Final stage of a cell division for eukaryotic cells both in mitosis and meiosis

Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized. Telophase accounts for approximately 2% of the cell cycle's duration.

<span class="mw-page-title-main">Cyclin</span> Group of proteins

Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

G<sub>2</sub> phase Second growth phase in the eukaryotic cell cycle, prior to mitosis

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">Cyclin E</span> Member of the cyclin family

Cyclin E is a member of the cyclin family.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

<span class="mw-page-title-main">Centrin</span> Family of calcium-binding phosphoproteins

Centrins, also known as caltractins, are a family of calcium-binding phosphoproteins found in the centrosome of eukaryotes. Centrins are small calcium binding proteins that are ubiquitous centrosome components. There are about 350 “signature” proteins that are unique to eukaryotic cells but have no significant homology to proteins in archaea and bacteria. They are a type of protein that is essential and present in almost all eukaryotic cells and are found in the centrioles and pericentriolar lattice. Human centrin genes are CETN1, CETN2 and CETN3.

<span class="mw-page-title-main">NEK2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.

<span class="mw-page-title-main">PCNT</span> Protein-coding gene in the species Homo sapiens

Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21. This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression. This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome.

<span class="mw-page-title-main">CEP170</span> Protein-coding gene in the species Homo sapiens

Centrosomal protein 170kDa, also known as CEP170, is a protein that in humans is encoded by the CEP170 gene.

<span class="mw-page-title-main">Pericentriolar material</span>

Pericentriolar material is a highly structured, dense mass of protein which makes up the part of the animal centrosome that surrounds the two centrioles. The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin, pericentrin and ninein.

Cdc14 and Cdc14 are a gene and its protein product respectively. Cdc14 is found in most of the eukaryotes. Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae. Cdc14 was later shown to encode a protein phosphatase. Cdc14 is dual-specificity, which means it has serine/threonine and tyrosine-directed activity. A preference for serines next to proline is reported. Many early studies, especially in the budding yeast Saccharomyces cerevisiae, demonstrated that the protein plays a key role in regulating late mitotic processes. However, more recent work in a range of systems suggests that its cellular function is more complex.

<span class="mw-page-title-main">CEP192</span> Protein-coding gene in the species Homo sapiens

Centrosomal protein of 192 kDa, also known as Cep192, is a protein that in humans is encoded by the CEP192 gene. It is the homolog of the C. elegans and D. melanogaster gene SPD-2.

Mitotic exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

References

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