Keep Calm and Carry on with Extra Centrosomes

Kalkan, Batuhan Mert; Özcan, Selahattin Can; Quintyne, Nicholas J.; Reed, Samantha L.; Acılan, Ceyda

doi:10.3390/cancers14020442

Cited by 17 publications

(14 citation statements)

References 257 publications

(337 reference statements)

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“…Previously, to our knowledge, maturation of amplified centrioles via PLK4 induction was depicted through illustrations which suggested that separate CRs were generated without any functional linkage between amplified centrosomes [16, 27]. In our proposed model (Fig 1H), we suggest that PLK4 induced CRCs should be linked to each other with centrosomal linker proteins until separation in prophase.…”

Section: Resultsmentioning

confidence: 58%

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Özcan,

Kalkan,

Çiçek

et al. 2023

Preprint

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he centrosome cycle is a tightly regulated process to ensure proper segregation of chromosomes. Not surprisingly, centriole number is tightly controlled via multiple mechanisms, one of which involves PLK4, an upstream kinase facilitating centriole biogenesis and duplication. Aberrations in this process can result in supernumerary centrosomes, which are frequently observed in a variety of cancers due to high levels of PLK4. Interestingly, extra centrosomes induced by PLK4 over-expression go through unique intermediate structures called the centrosome rosettes (CRs), where the mother centriole is surrounded by numerous daughter centrioles. The maturation and molecular nature of these CRs have not been investigated in detail. Upon prolonged PLK4 over-expression, cells exhibited large centrosomes that were clustered and contained more than two CRs, which we defined as centrosome rosette clusters (CRCs). As expected, these structures required high PLK4 levels at two consecutive cell cycles and were still interconnected with canonical centrosomal linker proteins such as C-Nap1, Rootletin, and Cep68. Knockout of these linker proteins resulted in distancing of CRs and CRCs as observed by increased diameter of the CRCs in interphase. In contrast, Nek2 knockout inhibited the separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. These results suggest a cell cycle dependent model for PLK4 induced centrosome amplification, which occurs in two consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.

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Section: Resultsmentioning

confidence: 58%

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Özcan,

Kalkan,

Çiçek

et al. 2023

Preprint

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“…For instance, cancer cells have found a way to deal with multiple centrosomes and still assemble a bipolar spindle even with more than two centrosomes. The mechanism named centrosome clustering consists by being able to form a bipolar spindle with one centrosome at one pole and three clustered centrosomes at the other pole [ 87 ]. Even if the mechanism is not fully understood, an inhibition of the clustering mechanism has been shown to be effective in eliminating cancer cells that have developed this strategy to proliferate in the presence of supernumerary centrosomes [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Duplication and Segregation of Centrosomes during Cell Division

Prigent

Uzbekov

2022

Cells

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During its division the cell must ensure the equal distribution of its genetic material in the two newly created cells, but it must also distribute organelles such as the Golgi apparatus, the mitochondria and the centrosome. DNA, the carrier of heredity, located in the nucleus of the cell, has made it possible to define the main principles that regulate the progression of the cell cycle. The cell cycle, which includes interphase and mitosis, is essentially a nuclear cycle, or a DNA cycle, since the interphase stages names (G1, S, G2) phases are based on processes that occur exclusively with DNA. However, centrosome duplication and segregation are two equally important events for the two new cells that must inherit a single centrosome. The centrosome, long considered the center of the cell, is made up of two small cylinders, the centrioles, made up of microtubules modified to acquire a very high stability. It is the main nucleation center of microtubules in the cell. Apart from a few exceptions, each cell in G1 phase has only one centrosome, consisting in of two centrioles and pericentriolar materials (PCM), which must be duplicated before the cell divides so that the two new cells formed inherit a single centrosome. The centriole is also the origin of the primary cilia, motile cilia and flagella of some cells.

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“…36 Cells with extra centrosomes undergoing bipolar division can sustain aneuploidy by merotelic attachments causing lagging chromosomes. 8,37 Still, the generation of aneuploidy at cell division does not necessarily mean that we obtain surviving cells with clonal chromosome alterations, since the aneuploid cell have to go into the cell cycle again and be allowed to pass through it, that is, a certain tolerance to aneuploidy is needed. It has previously been shown that defective TP53 affects the function of homologous recombination repair and nonhomologous end joining.…”

Section: Discussionmentioning

confidence: 99%

“…In cells with intact p53 function, multipolar cell division is often avoided by clustering of extra centrosomes 36 . Cells with extra centrosomes undergoing bipolar division can sustain aneuploidy by merotelic attachments causing lagging chromosomes 8,37 . Still, the generation of aneuploidy at cell division does not necessarily mean that we obtain surviving cells with clonal chromosome alterations, since the aneuploid cell have to go into the cell cycle again and be allowed to pass through it, that is, a certain tolerance to aneuploidy is needed.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of RB1, CDKN2A, and TP53 have distinct effects on genomic stability at side‐by‐side comparison in karyotypically normal cells

Andersson

Saba

Magnusson

et al. 2022

Genes Chromosomes & Cancer

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Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A, and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side‐by‐side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR‐Cas9 technology, RB1, CDKN2A, and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all three knockouts. Surprisingly, the RB1 and CDKN2A knocked out cell lines did not harbor more copy number aberrations than wild‐type cells, despite culturing for months. The TP53‐knocked out cells, in contrast, showed a massive amount of copy number alterations and saltatory evolution through whole genome duplication. This side‐by‐side comparison indicated that the effects on chromosomal stability from inactivation of RB1 and CDKN2A are negligible compared to inactivation of TP53, under the same conditions in a nonstressful environment, even though partly overlapping regulatory pathways are affected. Our data suggest that loss of RB1 and CDKN2A alone is not enough to trigger surviving detectable aneuploid clones while inactivation of TP53 on its own caused massive CIN leading to saltatory clonal evolution in vitro and clonal selection.

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Keep Calm and Carry on with Extra Centrosomes

Cited by 17 publications

References 257 publications

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Duplication and Segregation of Centrosomes during Cell Division

Inactivation of RB1, CDKN2A, and TP53 have distinct effects on genomic stability at side‐by‐side comparison in karyotypically normal cells

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