Dicentric breakage at telomere fusions

Pobiega, Sabrina; Marcand, Stéphane

doi:10.1101/gad.571510

Cited by 42 publications

(65 citation statements)

References 69 publications

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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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Section: Discussionmentioning

confidence: 92%

Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes inDrosophila melanogaster

Hill¹,

Golic

2015

Genetics

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“…To maximize its inactivation on galactose, a GAL1 promoter was inserted on each side of the centromere ( Fig. 1B; Pobiega and Marcand 2010). CEN6 inactivation will stabilize chromosome fusion between chromosome 6 and another chromosome.…”

Section: Conditional Dicentricsmentioning

confidence: 99%

“…CEN6 inactivation will stabilize chromosome fusion between chromosome 6 and another chromosome. In addition, it will create a positive selection for the fusions, since the missegregation of an unfused acentric chromosome 6 has a detrimental effect on cell growth, whereas chromosome fusion will rescue normal segregation and viability (Pobiega and Marcand 2010).…”

Section: Conditional Dicentricsmentioning

confidence: 99%

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Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions

et al. 2015

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Dicentric chromosomes are unstable products of erroneous DNA repair events that can lead to further genome rearrangements and extended gene copy number variations. During mitosis, they form anaphase bridges, resulting in chromosome breakage by an unknown mechanism. In budding yeast, dicentrics generated by telomere fusion break at the fusion, a process that restores the parental karyotype and protects cells from rare accidental telomere fusion. Here, we observed that dicentrics lacking telomere fusion preferentially break within a 25-to 30-kb-long region next to the centromeres. In all cases, dicentric breakage requires anaphase exit, ruling out stretching by the elongated mitotic spindle as the cause of breakage. Instead, breakage requires cytokinesis. In the presence of dicentrics, the cytokinetic septa pinch the nucleus, suggesting that dicentrics are severed after actomyosin ring contraction. At this time, centromeres and spindle pole bodies relocate to the bud neck, explaining how cytokinesis can sever dicentrics near centromeres.

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“…The remarkable size limitation of the amplified segments might be explained by the finding that a previously damaged chromosomal region remains susceptible for renewed breakage after fusion of DNA ends. 26 Combination of the main characteristics of BFB, random breakage of dicentrics and inheritance of the fragments by daughter cells, has important consequences for the genomic landscape in chromothripsis. Random break distribution, albeit restricted to a single dicentric chromosome, means that each round of division can position a rupture in a new genomic location; each mitosis thus contributes to the acquisition of additional CNum states by the cell population.…”

Section: Limiting Bfb To Single Chromosomesmentioning

confidence: 99%

Chromothripsis: Breakage-fusion-bridge over and over again

et al. 2013

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van Wely (2013) Chromothripsis: Breakage-fusion-bridge over and over again, Cell Cycle, 12:13, 2016-2023 T he acquisition of massive but localized chromosome translocations, a phenomenon termed chromothripsis, has received widespread attention since its discovery over a year ago. Until recently, chromothripsis was believed to originate from a single catastrophic event, but the molecular mechanisms leading to this event are yet to be uncovered. Because a thorough interpretation of the data are missing, the phenomenon itself has wrongly acquired the status of a mechanism used to justify many kinds of complex rearrangements. Although the assumption that all translocations in chromothripsis originate from a single event has met with criticism, satisfactory explanations for the intense but localized nature of this phenomenon are still missing. Here, we show why the data used to describe massive catastrophic rearrangements are incompatible with a model comprising a single event only and propose a molecular mechanism in which a combination of known cellular pathways accounts for chromothripsis. Instead of a single traumatic event, the protection of undamaged chromosomes by telomeres can limit repetitive breakage-fusion-bridge events to a single chromosome arm. Ultimately, common properties of chromosomal instability, such as aneuploidy and centromere fission, might establish the complex genetic pattern observed in this genomic state.

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Dicentric breakage at telomere fusions

Cited by 42 publications

References 69 publications

Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes inDrosophila melanogaster

Preferential Breakpoints in the Recovery of Broken Dicentric Chromosomes inDrosophila melanogaster

Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions

Chromothripsis: Breakage-fusion-bridge over and over again

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