Force-generating mechanisms of anaphase in human cells

Vukušić, Kruno; Buđa, Renata; Tolić, Iva Marija

doi:10.1242/jcs.231985

Cited by 56 publications

(44 citation statements)

References 156 publications

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“…Although the mechanism of spindle elongation in Naegleria is not yet established, the appearance of secondary bundles in the chromosome region is reminiscent of bridging fibers in other cell types (Simunić and Tolić, 2016). This similarity suggests that interactions between primary and secondary microtubule bundles may contribute to chromosome segregation (Vukušić, Buđa and Tolić, 2019).…”

Section: Discussionmentioning

confidence: 94%

“…In meiotic spindles, anaphase B is driven, at least in part, as polymerizing midzone microtubules interact with chromosomes (Dumont, Oegema and Desai, 2010; Danlasky et al , 2020). In mammalian cells, links between elongating midzone bridging microtubules and kinetochore fibers contribute to anaphase (Vukušić et al , 2017; Vukušić, Buđa and Tolić, 2019). Although the mechanism of spindle elongation in Naegleria is not yet established, the appearance of secondary bundles in the chromosome region is reminiscent of bridging fibers in other cell types (Simunić and Tolić, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Naegleria’smitotic spindles are built from unique tubulins and highlight core spindle features

Trupinić

Ivec

Swafford

et al. 2021

Preprint

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Naegleria gruberi is a unicellular eukaryote whose evolutionary distance from animals and fungi has made it useful for developing hypotheses about the last common eukaryotic ancestor. Naegleria amoebae lack a cytoplasmic microtubule cytoskeleton and assemble microtubules only during mitosis, and thus provides a unique system to study the evolution and functional specificity of mitotic tubulins and the resulting spindle. Previous studies showed that Naegleria amoebae express a divergent α-tubulin during mitosis and we now show that Naegleria amoebae express a second mitotic α- and two mitotic β-tubulins. The mitotic tubulins are evolutionarily divergent relative to typical α- and β- tubulins, contain residues that suggest distinct microtubule properties, and may represent drug targets for the "brain-eating amoeba" Naegleria fowleri. Using quantitative light microscopy, we find that Naegleria's mitotic spindle is a distinctive barrel-like structure built from a ring of microtubule bundles. Similar to those of other species, Naegleria's spindle is twisted and its length increases during mitosis suggesting that these aspects of mitosis are ancestral features. Because bundle numbers change during metaphase, we hypothesize that the initial bundles represent kinetochore fibers, and secondary bundles function as bridging fibers.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Naegleria’smitotic spindles are built from unique tubulins and highlight core spindle features

Trupinić

Ivec

Swafford

et al. 2021

Preprint

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“…Although much of chromosome dynamics is driven by the kinetochore, numerous studies reveal additional forces act on the chromosomes during mitosis [52]. Here we focused on the role of kinetochore independent forces driving sister chromatid separation.…”

Section: Discussionmentioning

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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“…The process of chromosome segregation relies on forces generated by the interaction of the kinetochore (the multiprotein structure that forms on centromeric chromatin) with spindle microtubules [16,79,80]. After the nuclear envelope breakdown, microtubules nucleated from spindle poles grow and shorten rapidly in the cellular space, randomly contacting kinetochores [12].…”

Section: Roles Of Kinetochores In Chromosome Segregation and Mitotic mentioning

confidence: 99%

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Degrassi

Damizia

Lavia

2019

Cells

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Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.

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Force-generating mechanisms of anaphase in human cells

Cited by 56 publications

References 156 publications

Naegleria’smitotic spindles are built from unique tubulins and highlight core spindle features

Naegleria’smitotic spindles are built from unique tubulins and highlight core spindle features

Kinetochore-independent mechanisms of sister chromosome separation

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

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