Centromere-Independent Accumulation of Cohesin at Ectopic Heterochromatin Sites Induces Chromosome Stretching during Anaphase

Oliveira, Raquel; Kotadia, Shaila; Tavares, Alexandra; Mirkovic, Mihailo; Bowlin, Katherine; Eichinger, Christian; Nasmyth, Kim; Sullivan, William M.

doi:10.1371/journal.pbio.1001962

Cited by 34 publications

(37 citation statements)

References 55 publications

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“…Based on this result, and the small number of anaphases observed, there is no evidence that hybrid lethality results from centromere or kinetochore dysfunction (Figure 9). We did, however, identify defects in chromosome condensation and integrity in hybrid males that are reminiscent of those observed in cells depleted of condensins or showing abnormal accumulations of cohesins ( Figure 8) (Bhat et al 1996;Steffensen et al 2001;Dej et al 2003;Somma et al 2003;Cobbe et al 2006;Savvidou et al 2005;Oliveira et al 2014). Interestingly, these defects have been shown to interfere with sister chromatid separation leading to anaphase bridges.…”

Section: Hmr and Lhr Have A Role In Sister Chromatid Separation Durinmentioning

confidence: 71%

The Hybrid Incompatibility Genes Lhr and Hmr Are Required for Sister Chromatid Detachment During Anaphase but Not for Centromere Function

et al. 2017

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Crosses between females and males produce hybrid sons that die at the larval stage. This hybrid lethality is suppressed by loss-of-function mutations in the () or in the () genes. Previous studies have shown that Hmr and Lhr interact with heterochromatin proteins and suppress expression of transposable elements within It also has been proposed that Hmr and Lhr function at the centromere. We examined mitotic divisions in larval brains from and single mutants and; double mutants in In none of the mutants did we observe defects in metaphase chromosome alignment or hyperploid cells, which are hallmarks of centromere or kinetochore dysfunction. In addition, we found that Hmr-HA and Lhr-HA do not colocalize with centromeres either during interphase or mitotic division. However, all mutants displayed anaphase bridges and chromosome aberrations resulting from the breakage of these bridges, predominantly at the euchromatin-heterochromatin junction. The few dividing cells present in hybrid males showed fuzzy and irregularly condensed chromosomes with unresolved sister chromatids. Despite this defect in condensation, chromosomes in hybrids managed to align on the metaphase plate and undergo anaphase. We conclude that there is no evidence for a centromeric function of Hmr and Lhr within nor for a centromere defect causing hybrid lethality. Instead, we find that and are required in for detachment of sister chromatids during anaphase.

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Section: Hmr and Lhr Have A Role In Sister Chromatid Separation Durinmentioning

confidence: 71%

The Hybrid Incompatibility Genes Lhr and Hmr Are Required for Sister Chromatid Detachment During Anaphase but Not for Centromere Function

et al. 2017

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“…Based on this result and the small number of anaphases observed, there is no evidence that hybrid lethality results from centromere or kinetochore dysfunction (Figure 9). We did though identify defects in chromosome condensation and integrity in hybrid males that are reminiscent of those observed in cells depleted of condensins or showing abnormal accumulations of cohesins (Figure 8;Bhat et al, 1996;Steffensen et al, 2001;Somma et al, 2003;Cobbe et al, 2006;Savvidou et al 2006;Oliveira et al, 2014). Interestingly, these defects have been shown to interfere with sister chromatid separation leading to anaphase bridges.…”

Section: Do Hybrids Have a Mitotic Defect Similar To The Hmr And Lhr mentioning

confidence: 83%

“…Notably, the Drosophila cohesin-loading factor Nipped-B (NIPBL/Scc2) accumulates in heterochromatin including the ectopic heterochromatin regions generated by translocations. Germane to Hmr and Lhr loss of function phenotype, Nipped-B/cohesin accumulation in these regions delays sister chromatid separation during anaphase, leading to stretched chromatids that bridge the two segregating chromosome sets (Oliveira et al, 2014).…”

Section: Hmr and Lhr Have A Role In Sister Chromatid Separation Durinmentioning

confidence: 99%

LhrandHmrare required for sister chromatid detachment during anaphase but not for centromere function

Bonaccorsi

Marzullo

et al. 2017

Preprint

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“…Once removed, microtubules drive sister separation [29]. The delay in cohesin removal does not depend on proximity to the centromere, as it occurs in chromosome rearrangements in which the centric heterochromatin is no longer associated with the centromere [30].…”

Section: Acentric Sister Separation But Not Cohesin Removal Is Delamentioning

confidence: 99%

Kinetochore-independent mechanisms of sister chromosome separation

Vicars

Karg

Warecki

et al. 2020

Preprint

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Although centromeres play a key role in sister chromatid separation and segregation, mitotic transmission of chromosome fragments lacking a centromere (acentrics) can be successful. In Drosophila neuroblasts, acentric chromosomes undergo delayed, but successful transmission revealing the existence of kinetochore-independent mechanisms driving transmission. In spite of delayed sister chromatid separation, bulk cohesin removal from the acentric is not delayed, suggesting factors other than cohesin are responsible for the delay. In contrast to intact kinetochore-bearing chromosomes, we discovered that acentrics align parallel as well as perpendicular to the mitotic spindle. In addition, sister acentrics undergo unconventional patterns of separation. For example, rather than the simultaneous separation of sisters, acentrics oriented parallel to the spindle often slide past one another toward opposing poles. To identify the mechanisms driving acentric separation, we screened 117 RNAi gene knockdowns for synthetic lethality with acentric chromosome fragments. In addition to well-established DNA repair and checkpoint mutants, this candidate screen identified synthetic lethality with X-chromosome-derived acentric fragments in knockdowns of Greatwall (cell cycle kinase), EB1 (plus-end tracking protein), and Map205 (microtubule-stabilizing protein). Additional image-based screening revealed that reductions in Topoisomerase II levels disrupted sister acentric separation. Intriguingly, live imaging revealed that knockdowns of EB1, Map205, and Greatwall preferentially disrupted the sliding mode of sister acentric separation. In spite of these failures in acentric separation, acentrics incorporated into daughter nuclei and there was no increase in micronuclei formation. Based on our analysis of EB1 localization and knockdown phenotypes, we propose that in the absence of a kinetochore, microtubule plus-end dynamics provide the force to resolve DNA catenations required for sister separation.AUTHOR SUMMARYCentromeres, the site on the chromosomes to which microtubules attach driving the separation and segregation of replicated sister chromosomes, have been viewed as essential for proper cell division and accurate transmission of chromosomes into daughter cells. However previous studies demonstrated that sister chromosomes lacking a centromere (acentrics) often undergo separation, segregation and transmission. Here we demonstrate that sister acentrics are held together through DNA intertwining. During anaphase, acentric sister separation is achieved through Topoisomerase activity, an enzyme that resolves these DNA linkages, as well as forces generated on the acentrics by the growing ends of highly dynamic microtubule polymers. We found acentric sister chromatids display unique patterns of separation using mechanisms independent of the centromere. Additionally, we identified the specific microtubule-associated proteins required for the successful mitotic transmission of acentric chromosomes to daughter cells. These studies reveal unsuspected, distinct forces that likely act on all chromosomes during mitosis independent of centromere-microtubule attachments.

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Centromere-Independent Accumulation of Cohesin at Ectopic Heterochromatin Sites Induces Chromosome Stretching during Anaphase

Abstract: Live imaging of cells carrying rearranged chromosomes shows that misplaced heterochromatin is sufficient to induce ectopic cohesion and chromosome stretching during mitosis, and may compromise genetic stability.

Cited by 34 publications

References 55 publications

The Hybrid Incompatibility Genes Lhr and Hmr Are Required for Sister Chromatid Detachment During Anaphase but Not for Centromere Function

The Hybrid Incompatibility Genes Lhr and Hmr Are Required for Sister Chromatid Detachment During Anaphase but Not for Centromere Function

LhrandHmrare required for sister chromatid detachment during anaphase but not for centromere function

Kinetochore-independent mechanisms of sister chromosome separation

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