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Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.

Pihan GA - Front Oncol (2013)

Bottom Line: But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells.Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling.Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

No MeSH data available.


Related in: MedlinePlus

Chromoanagenesis in cancer. Complex structural chromosome rearrangements in cancer, involve stepwise or punctual chromosome restructuring. It includes stepwise classic intra or inter-chromosomal break-fusion-bridge cycles (A); chromothripsis (B), which are punctual localized highly complex chromosome fragmentation (1) and rejoining (2) events, and chromoplexy (C), in which complex linked translocation events involving multiple chromosomes presumably occur simultaneously. 1 through 6 (black typeface) and 1 through 5 (orange typeface) represent two such linked “chained” events.
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Figure 7: Chromoanagenesis in cancer. Complex structural chromosome rearrangements in cancer, involve stepwise or punctual chromosome restructuring. It includes stepwise classic intra or inter-chromosomal break-fusion-bridge cycles (A); chromothripsis (B), which are punctual localized highly complex chromosome fragmentation (1) and rejoining (2) events, and chromoplexy (C), in which complex linked translocation events involving multiple chromosomes presumably occur simultaneously. 1 through 6 (black typeface) and 1 through 5 (orange typeface) represent two such linked “chained” events.

Mentions: In CIN, numerical (nCIN) and structural (sCIN) chromosome abnormalities nearly always co-exist [reviewed in Ref. (362–365)]. nCIN includes a spectrum of gain and losses of chromosomes fragments from kilobases to megabases, whole arms or even entire chromosomes. sCIN include translocations, inversions, end-fusions, and a number of more complex rearrangements. With the exception of break-fusion-bridge (BFB) cycles (366) (Figure 7), until recently it was thought that nCIN and sCIN, despite their frequent coexistence, were largely mechanistically unrelated. Several recent whole-genome sequencing studies of cancer tissue have uncovered new mechanistic links between nCIN, sCIN, and centrosomes (Figure 7). Grouped under the term chromoanagenesis (chromosome rebirth) (367), the first class of sCIN consists of a handful of apparently random chromosome loci per genome with highly complex structural (and copy number) sequence alterations including sequence duplications, deletions, scrambling, and polarity reversals, as if the segment had been broken in hundreds of fragments and rejoined more or less randomly (Figure 7). This phenomenon has been termed chromothripsis (chromosome shattering) (368). Chromothripsis has been postulated to occur as a single, punctual, massive event, rather than sequentially, as is seen with BFB cycles. Two possible causative mechanisms have been thus far delineated, both of which are enabled by chromosome missegregation events triggered by abnormal centrosome function in mitosis. Chromothripsis involves premature mitotic entry of a chromosome contained in a micronucleus that resulted from a chromosome missegregation event in the previous mitosis (368, 369). Mitotic entry, before completion of DNA replication in the micronucleus, leads to failure of micronucleus envelope breakdown, mitotic transit with random segregation to daughter cells, and random reassembly of the incompletely replicated chromosome fragments within the micronucleus during the subsequent interphase (368, 369). Chromothripsis [reviewed in (362, 363, 370)] appears to be common in carcinoma and neural tumors (369, 371) and is the mechanism most likely to operate in micronuclei. Micronuclei in cancer are frequent and may have many origins, one of the most important of which appears to be merotelic chromosome orientation at metaphase. A merothelic chromosome is one in which one of its two kinetochores is simultaneously attached by microtubules to the two spindle poles. Merothelic chromosomes often lag at the center of the dividing cell at anaphase and are usually not incorporated within the two groups of chromosomes at the poles in telophase before reassembly of the nuclear envelope at the end of mitosis, becoming independent “micronuclei.” Notably, a transient state of mitotic spindle multipolarity in cells with supernumerary centrosomes is thought to be the most important cause of merothelic chromosome attachment and micronuclei formation (355) (vide infra), again implicating centrosome dysfunction in the cause of sCIN.


Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.

Pihan GA - Front Oncol (2013)

Chromoanagenesis in cancer. Complex structural chromosome rearrangements in cancer, involve stepwise or punctual chromosome restructuring. It includes stepwise classic intra or inter-chromosomal break-fusion-bridge cycles (A); chromothripsis (B), which are punctual localized highly complex chromosome fragmentation (1) and rejoining (2) events, and chromoplexy (C), in which complex linked translocation events involving multiple chromosomes presumably occur simultaneously. 1 through 6 (black typeface) and 1 through 5 (orange typeface) represent two such linked “chained” events.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824400&req=5

Figure 7: Chromoanagenesis in cancer. Complex structural chromosome rearrangements in cancer, involve stepwise or punctual chromosome restructuring. It includes stepwise classic intra or inter-chromosomal break-fusion-bridge cycles (A); chromothripsis (B), which are punctual localized highly complex chromosome fragmentation (1) and rejoining (2) events, and chromoplexy (C), in which complex linked translocation events involving multiple chromosomes presumably occur simultaneously. 1 through 6 (black typeface) and 1 through 5 (orange typeface) represent two such linked “chained” events.
Mentions: In CIN, numerical (nCIN) and structural (sCIN) chromosome abnormalities nearly always co-exist [reviewed in Ref. (362–365)]. nCIN includes a spectrum of gain and losses of chromosomes fragments from kilobases to megabases, whole arms or even entire chromosomes. sCIN include translocations, inversions, end-fusions, and a number of more complex rearrangements. With the exception of break-fusion-bridge (BFB) cycles (366) (Figure 7), until recently it was thought that nCIN and sCIN, despite their frequent coexistence, were largely mechanistically unrelated. Several recent whole-genome sequencing studies of cancer tissue have uncovered new mechanistic links between nCIN, sCIN, and centrosomes (Figure 7). Grouped under the term chromoanagenesis (chromosome rebirth) (367), the first class of sCIN consists of a handful of apparently random chromosome loci per genome with highly complex structural (and copy number) sequence alterations including sequence duplications, deletions, scrambling, and polarity reversals, as if the segment had been broken in hundreds of fragments and rejoined more or less randomly (Figure 7). This phenomenon has been termed chromothripsis (chromosome shattering) (368). Chromothripsis has been postulated to occur as a single, punctual, massive event, rather than sequentially, as is seen with BFB cycles. Two possible causative mechanisms have been thus far delineated, both of which are enabled by chromosome missegregation events triggered by abnormal centrosome function in mitosis. Chromothripsis involves premature mitotic entry of a chromosome contained in a micronucleus that resulted from a chromosome missegregation event in the previous mitosis (368, 369). Mitotic entry, before completion of DNA replication in the micronucleus, leads to failure of micronucleus envelope breakdown, mitotic transit with random segregation to daughter cells, and random reassembly of the incompletely replicated chromosome fragments within the micronucleus during the subsequent interphase (368, 369). Chromothripsis [reviewed in (362, 363, 370)] appears to be common in carcinoma and neural tumors (369, 371) and is the mechanism most likely to operate in micronuclei. Micronuclei in cancer are frequent and may have many origins, one of the most important of which appears to be merotelic chromosome orientation at metaphase. A merothelic chromosome is one in which one of its two kinetochores is simultaneously attached by microtubules to the two spindle poles. Merothelic chromosomes often lag at the center of the dividing cell at anaphase and are usually not incorporated within the two groups of chromosomes at the poles in telophase before reassembly of the nuclear envelope at the end of mitosis, becoming independent “micronuclei.” Notably, a transient state of mitotic spindle multipolarity in cells with supernumerary centrosomes is thought to be the most important cause of merothelic chromosome attachment and micronuclei formation (355) (vide infra), again implicating centrosome dysfunction in the cause of sCIN.

Bottom Line: But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells.Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling.Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

No MeSH data available.


Related in: MedlinePlus