| Cell biology | |
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| centrosome | |
.svg) Components of a typical centrosome:
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Thecentrosome (Latin centrum 'centre' + Greek sōma 'body') (archaically cytocentre[1]) is a non-membrane boundedorganelle in theanimal cell[2] that serves as the mainmicrotubule organizing centre (MTOC) and a regulator ofcell-cycle progression. The centrosome provides structure for the cell. It is thought to have evolved only in themetazoan lineage ofeukaryotic cells.[3]Fungi andplants lack centrosomes and therefore use other structures to organize their microtubules.[4][5] Although the centrosome has a key role in efficientmitosis in animalcells, it is not essential in certain fly andflatworm species.[6][7][8]
In non-rodent mammals thesperm contributes the major part of the centrosome, thecentrioles.[2] Centrosomes are composed of two centrioles arranged atright angles to each other, and surrounded by a dense, highly structured[9] mass ofproteins termed thepericentriolar material (PCM). The PCM contains proteins responsible formicrotubule nucleation and anchoring[10] — includingγ-tubulin,pericentrin andninein. In general, each centriole of the centrosome is based on a nine-triplet microtubule assembled in a cartwheel structure, and containscentrin,cenexin andtektin.[11]In many cell types, the centrosome is replaced by acilium during cellular differentiation. However, once the cell starts to divide, the cilium is replaced again by the centrosome.[12]
The centrosome was discovered jointly byWalther Flemming in 1875[13][14] andEdouard Van Beneden in 1876,[15][14] and later described and named in 1888 byTheodor Boveri.[16]
Centrosomes are associated with thenuclear membrane during theprophase stage of the cell cycle. Duringmitosis, the nuclear membrane breaks down, and the centrosome-nucleatedmicrotubules can interact with thechromosomes to build themitotic spindle.
The mother centriole, the older of the two in the centriole pair, also has a central role in makingcilia andflagella.[11]
The centrosome is copied only once percell cycle, so that each daughter cell inherits one centrosome, containing two structures called centrioles. The centrosome replicates during theS phase of the cell cycle. During theprophase in the process of cell division calledmitosis, the centrosomes migrate to opposite poles of the cell. The mitotic spindle then forms between the two centrosomes. Upon division, each daughter cell receives one centrosome. Aberrant numbers of centrosomes in a cell have been associated withcancer. Doubling of a centrosome is similar toDNA replication in two respects: thesemiconservative nature of the process and the action ofCDK2 as a regulator of the process.[17] But the processes are essentially different in that centrosome doubling does not occur by template reading and assembly. The mother centriole just aids in the accumulation of materials required for the assembly of the daughter centriole.[18]
Centrioles, however, are not required for the progression of mitosis. When the centrioles are irradiated by a laser, mitosis proceeds normally with a morphologically normal spindle. Moreover, development of thefruit flyDrosophila is largely normal when centrioles are absent due to a mutation in a gene required for their duplication.[19] In the absence of the centrioles, the microtubules of the spindle are focused bymotors, allowing the formation of a bipolar spindle. Many cells can completely undergo interphase without centrioles.[11]
Unlike centrioles, centrosomes are required for survival of the organism. Cells without centrosomes lack radial arrays ofastral microtubules. They are also defective in spindle positioning and in the ability to establish a central localization site in cytokinesis. The function of centrosomes in this context is hypothesized to ensure the fidelity ofcell division, because it greatly increases the efficacy. Some cell types arrest in the following cell cycle when centrosomes are absent. This is not a universal phenomenon.
When the nematodeC. elegans egg is fertilized, the sperm delivers a pair of centrioles. These centrioles will form the centrosomes, which will direct the first cell division of thezygote, and this will determine its polarity. It's not yet clear whether the role of the centrosome in polarity determination is microtubule-dependent or independent.
In human reproduction, thesperm supplies the centriole that creates the centrosome and microtubule system of the zygote.[20] Some failures infertilization are centrosome-related.[2]
Theodor Boveri, in 1914, described centrosome aberrations incancer cells. This initial observation was subsequently extended to many types of human tumors.[21] Centrosome alterations in cancer can be divided in two subgroups — i.e., structural or numeric aberrations — yet both can be found simultaneously in a tumor.
Usually, structural aberrations appear due to uncontrolled expression of centrosome components, or due to post-translational modifications (such as phosphorylations) that are not adequate for the components. These modifications may produce variations in centrosome size (usually too large, due to an excess of pericentriolar material). In addition, because centrosomal proteins have a tendency to form aggregates, centrosome-related bodies (CRBs) are often observed in ectopic places.[22] Both enlarged centrosomes and CRBs are similar to the centrosomal structures observed in tumors.[23] Even more, these structures can be induced in culture cells by overexpression of specific centrosomal proteins, such as CNap-1 or Nlp.[22][24] These structures may look very similar, yet detailed studies reveal that they may present very different properties, depending on their proteic composition. For instance, their capacity to incorporate γ-TuRC complexes (see also:γ-tubulin) can be very variable, and so their capacity to nucleatemicrotubules[23] therefore affects the shape, polarity and motility of implicated tumor cells in different ways.
The presence of an inadequate number of centrosomes is very often linked to the appearance ofgenome instability and the loss of tissue differentiation.[23][25] However, the method to count the centrosome number (with two centrioles to each centrosome) is often not very precise, because it is frequently assessed usingfluorescence microscopy, which does not have high enoughoptical resolution to resolve centrioles that are very close to each other. Nevertheless, it is clear that the presence of an excess of centrosomes is a common event in human tumors. It has been observed that loss of thetumor-suppressor p53 produces superfluous centrosomes,[26] as well as deregulating other proteins implicated incancer formation in humans, such asBRCA1 andBRCA2. (For references, see[21].) An excess of centrosomes can be generated by very different mechanisms: specific reduplication of the centrosome, cytokinesis failure duringcell division (generating an increase in chromosome number), cell fusion (such as in cases of infection by specific viruses) orde novo generation of centrosomes. At this point, there is insufficient information to know how prevalent these mechanisms arein vivo, but it is possible that the increase in centrosome numbers due to a failure during cell division might be more frequent than appreciated, because many "primary" defects in one cell (deregulation of thecell cycle, defectiveDNA orchromatin metabolism, failure in thespindle checkpoint, etc.) would generate a failure in cell division, an increase inploidy and an increase in centrosome numbers as a "secondary" effect.[27][28]
Theevolutionary history of the centrosome and thecentriole has been traced for some of the signature genes — e.g., thecentrins.[3] Centrins participate incalcium signaling and are required for centriole duplication.[29] There exist two main subfamilies of centrins, both of which are present in the early-branchingeukaryoteGiardia intestinalis. Centrins have therefore been present in the common ancestor of eukaryotes. Conversely, they have no recognizablehomologs inarchea andbacteria and are thus part of the "eukaryotic signature genes". Although there are studies on the evolution of the centrins and centrioles,[3][30] no studies have been published on the evolution of thepericentriolar material.
It is evident that some parts of the centrosome are highly diverged in the model speciesDrosophila melanogaster andCaenorhabditis elegans. For example, both species have lost one of the centrin subfamilies that are usually associated with centriole duplication.Drosophila melanogaster mutants that lack centrosomes can even develop to morphologically normal adult flies, which then die shortly after birth because their sensory neurons lackcilia.[19] Thus, these flies have evolved functionally redundant machinery, which is independent of the centrosomes.
Research in 2006 indicated that centrosomes fromAtlantic surf clam eggs containRNA sequences. The sequences identified were found in "few to no" other places in the cell, and do not appear in existinggenome databases. One identified RNA sequence contains a putativeRNA polymerase, leading to the hypothesis of an RNA-based genome within the centrosome.[31] However, subsequent research has shown that centrosome do not contain their own DNA-based genomes. While it was confirmed that RNA molecules associate with centrosomes, the sequences have still been found within the nucleus. Furthermore, centrosomes can formde novo after having been removed (e.g., by laser irradiation) from normal cells.[30]
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