Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions

López, Virginia; Barinova, Natalja; Onishi, Masayuki; Pobiega, Sabrina; Pringle, John R.; Dubrana, Karine; Marcand, Stéphane

doi:10.1101/gad.254664.114

Cited by 54 publications

(71 citation statements)

References 76 publications

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“…This study used live-cell imaging to determine the fate of dicentric chromosomes formed during telomere crisis and showed that dicentric chromosomes do not break during mitosis. This finding was in agreement with work in yeast cells and a subsequent analysis in human cells 3,103,104 (FIG. 5a).…”

Section: Telomere Crisis and Genome Instabilitysupporting

confidence: 92%

Telomeres in cancer: tumour suppression and genome instability

Maciejowski

Lange

2017

Nat Rev Mol Cell Biol

590

495

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The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.

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Section: Telomere Crisis and Genome Instabilitysupporting

confidence: 92%

Telomeres in cancer: tumour suppression and genome instability

Maciejowski

Lange

2017

Nat Rev Mol Cell Biol

590

495

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“…Indeed, when ingression was blocked with the actomyosin inhibitor blebbistatin (Straight et al, 2003), the dicentric chromosomes clearly remained intact (0/24 events) (Figure 1F; MovieS1, panel 1). Thus, as is the case in budding yeast (Haber et al, 1984; Lopez et al, 2015; Hill and Bloom, 1989), mammalian dicentric chromosomes can withstand the forces of the mitotic spindle and do not break before cytokinesis. This result is not unexpected given that the spindle force (0.5-1.5 nN) is insufficient to break a mitotic chromosome, which can withstand at least 100 nN (Houchmandzadeh et al, 1997).…”

Section: Resultsmentioning

confidence: 84%

Chromothripsis and Kataegis Induced by Telomere Crisis

Maciejowski

Bosco

et al. 2015

Cell

597

714

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Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 h after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.

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“…We suggest that nonrandom breakage of the dicentric chromosome, as has been seen in other organisms (Shimizu et al 2005;Pobiega and Marcand 2010;Song et al 2013;Lopez et al 2015), is the most likely explanation for the clustered locations of new telomeres. If breakage in euchromatin tends to occur at a few preferred sites, then viable twobreak combinations should be much more frequent than if breakage were random.…”

Section: Discussionmentioning

confidence: 92%

Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes inDrosophila melanogaster

Hill¹,

Golic

2015

Genetics

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We designed a system to determine whether dicentric chromosomes in Drosophila melanogaster break at random or at preferred sites. Sister chromatid exchange in a Ring-X chromosome produced dicentric chromosomes with two bridging arms connecting segregating centromeres as cells divide. This double bridge can break in mitosis. A genetic screen recovered chromosomes that were linearized by breakage in the male germline. Because the screen required viability of males with this X chromosome, the breakpoints in each arm of the double bridge must be closely matched to produce a nearly euploid chromosome. We expected that most linear chromosomes would be broken in heterochromatin because there are no vital genes in heterochromatin, and breakpoint distribution would be relatively unconstrained. Surprisingly, approximately half the breakpoints are found in euchromatin, and the breakpoints are clustered in just a few regions of the chromosome that closely match regions identified as intercalary heterochromatin. The results support the Laird hypothesis that intercalary heterochromatin can explain fragile sites in mitotic chromosomes, including fragile X. Opened rings also were recovered after male larvae were exposed to X-rays. This method was much less efficient and produced chromosomes with a strikingly different array of breakpoints, with almost all located in heterochromatin. A series of circularly permuted linear X chromosomes was generated that may be useful for investigating aspects of chromosome behavior, such as crossover distribution and interference in meiosis, or questions of nuclear organization and function.KEYWORDS dicentric chromosome; intercalary heterochromatin; fragile X; FLP D ROSOPHILA is noted for a combination of facile genetics and high-resolution cytology that allows the recovery and characterization of a variety of chromosome rearrangements. Simple structural changes such as duplications, deficiencies, inversions, and translocations are readily produced through a variety of classical and modern techniques. More complex rearrangements such as balancers, compound chromosomes, and ring chromosomes also have been generated. Ring chromosomes historically have been of interest for a number of unique properties, such as a propensity for loss during early embryonic mitoses and dominant zygotic lethality (Leigh 1976;Ashburner et al. 2005). Despite their "instability," ring chromosome stocks can be remarkably stable, with very few reported instances of spontaneous opening into linear chromosomes.In this work, we produced a number of linearized ring chromosomes. One goal was to determine whether there are preferred sites of breakage for dicentric chromosomes. Although we have previously shown that dicentric Y, 3, and 4 chromosomes can break and heal in the male germline and be recovered in offspring, these chromosomes allowed little opportunity to determine whether there were preferred sites of breakage (Ahmad and Golic 1998; Golic 2008, 2010;Titen et al. 2014). In the case of the Y chromosome, low r...

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Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions

Cited by 54 publications

References 76 publications

Telomeres in cancer: tumour suppression and genome instability

Telomeres in cancer: tumour suppression and genome instability

Chromothripsis and Kataegis Induced by Telomere Crisis

Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes inDrosophila melanogaster

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