The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation

Karg, Travis; Elting, Mary Williard; Vicars, Hannah; Dumont, Sophie; Sullivan, William M.

doi:10.1083/jcb.201604079

Cited by 20 publications

(54 citation statements)

References 49 publications

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“…Thus, alternative mechanisms for congression of the eliminated DNA to the metaphase plate must be involved since the DNA lacks CENP-A and kinetochores [28]. These mechanisms could include the contribution of polar ejection forces involving dynamic instability of poleinitiated MTs, plus-end directed chromokinesins, the contribution of interpolar microtubules, or scaffolding or tethering proteins within the spindle [72][73][74][75][76][77].…”

Section: Timing Of Dna Breaksmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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Germline and somatic genomes are typically the same in a multicellular organism. However, in some organisms including the parasitic nematode Ascaris, programmed DNA elimination leads to a reduced somatic genome compared to germline cells. Previous work on the parasitic nematode Ascaris demonstrated that programmed DNA elimination encompasses high fidelity chromosomal breaks at specific genome locations and loss of specific genome sequences including a major tandem repeat of 120 bp and ~1,000 germline-expressed genes. However, the precise chromosomal locations of the 120 bp repeats, the breaks regions, and the eliminated genes remained unknown. Here, we used PacBio longread sequencing and chromosome conformation capture (Hi-C) to obtain fully assembled chromosomes of Ascaris germline and somatic genomes, enabling a complete chromosomal view of DNA elimination.Surprisingly, we found that all 24 germline chromosomes undergo comprehensive chromosome end remodeling with DNA breaks in their subtelomeric regions and loss of distal sequences including the telomeres at both chromosome ends. All new Ascaris somatic chromosome ends are recapped by de novo telomere healing. We provide an ultrastructural analysis of DNA elimination and show that Ascaris eliminated DNA is incorporated into many double membrane-bound structures, similar to micronuclei, during telophase of a DNA elimination mitosis. These micronuclei undergo dynamic changes including loss of active histone marks and localize to the cytoplasm following daughter nuclei formation and cytokinesis where they form autophagosomes. Comparative analysis of nematode chromosomes suggests that germline chromosome fusions occurred forming Ascaris sex chromosomes that become independent chromosomes following DNA elimination breaks in somatic cells. These studies provide the first chromosomal view and define novel features and functions of metazoan programmed DNA elimination.

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Section: Timing Of Dna Breaksmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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“…Spindle forces and motor proteins drive chromosome movement during mitosis, but these do not engage chromosome fragments lacking a centromere. In Drosophila neuroblasts, acentric chromosomal fragments have been reported to partially segregate poleward [56] through kinetochore-independent microtubules and the chromokinesin Klp3a [57], which shares similarity to human KIF4A. Alternative models include the topological linkage or “tethering” of chromosome fragments to each other, as suggested by 5/8 Look-Seq examples in which the majority of fragments were unequally distributed to a single daughter [25], or perhaps onto other chromosomes, a mechanism analogous to the proposal that extrachromosomal DNAs (including DMs or viral episomes) could tether and segregate in trans with centromere-containing chromosomes [58–60].…”

Section: Bringing It All Back Home: Reassembly Through Dna Repairmentioning

confidence: 99%

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Cleveland

2017

Trends in Cell Biology

175

166

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Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome missegregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are re-ligated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.

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“…Despite the inability of acentric chromosomes to form kinetochore-microtubule attachments, studies show that while some acentrics fail to segregate properly [8], others are capable of efficient poleward segregation [18,24,62,[64][65][66][67]. Failure of acentrics to reincorporate into daughter telophase nuclei leads to the formation of micronuclei, which can cause aneuploidy or DNA damage, and are a hallmark of cancer [9][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…In Drosophila, acentric behavior has been studied using transgenic flies containing a heat-shock inducible I-CreI endonuclease [18][19][20][21][22][23][24], which targets rDNA near the base of the X chromosome and creates double-stranded DNA breaks [20,[25][26][27]. I-CreImediated DNA breaks result in γH2Av foci that persist through mitosis and chromosome fragments that do not recruit canonical centromere components and thus are considered acentrics [18].…”

Section: Introductionmentioning

confidence: 99%

“…Even though I-CreI-induced acentrics initially lag on the metaphase plate while undamaged chromosomes segregate, acentrics ultimately undergo delayed but successful segregation [18]. Acentric segregation is achieved through protein-coated DNA tethers connecting acentrics to their centric partners and microtubule bundles that encompass acentrics, enabling their poleward movement [24]. The histone-based DNA tether is associated with Polo, BubR1, and the chromosome passenger proteins Aurora B and INCENP [18].…”

Section: Introductionmentioning

confidence: 99%

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Aurora B-mediated exclusion of HP1a from latesegregating chromatin prevents formation of micronuclei

Warecki

Sullivan

2018

Preprint

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Late-segregating acentric chromosomes pose a serious risk to genomic integrity when they are excluded from dividing daughter nuclei and form damage-prone micronuclei. Insight into the cellular mechanisms that prevent the formation of micronuclei from acentrics come from studies demonstrating that acentrics reincorporate into daughter telophase nuclei by passing through Aurora B kinase-dependent channels in the nuclear envelope of Drosophila neuroblasts. Here, we uncover a mechanism of nuclear envelope channel formation in which localized concentrations of Aurora B preferentially phosphorylate H3(S10) on heterochromatic acentrics and their associated DNA tethers. This phosphorylation event prevents HP1a from associating with heterochromatin and results in localized inhibition of nuclear envelope reassembly on endonuclease-and Xirradiation-induced acentrics and the main daughter nuclei at the sites of acentric entry to promote the formation of channels. Finally, we find that HP1a also specifies initiation sites of nuclear envelope reassembly on undamaged chromatin. Taken together, these results demonstrate that Aurora B-mediated regulation of HP1a-chromatin interactions plays a key role maintaining genome integrity by locally preventing nuclear envelope assembly and facilitating incorporation of late-segregating acentrics into daughter nuclei.

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The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation

Cited by 20 publications

References 49 publications

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Aurora B-mediated exclusion of HP1a from latesegregating chromatin prevents formation of micronuclei

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