An anaphase surveillance mechanism prevents micronuclei formation from mitotic errors

Orr, Bernardo; Sousa, Filipe; Gomes, Mónica; Ferreira, Luísa T.; Figueiredo, Ana C.; Maiato, Hélder

doi:10.1101/2021.02.26.433009

Cited by 7 publications

(13 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data reveal that Aurora B activity is involved in the active correction of lazy kinetochores in early anaphase. This is distinct from any proposed roles of Aurora B in late anaphase 63,64 , and defines a new layer of error correction. In pre-anaphase cells, Aurora B located within the centromere-kinetochore mediates the destabilization of improper microtubule-kinetochore attachments, which are normally under low tension, rendering the kinetochores unattached 65 .…”

Section: Discussionmentioning

confidence: 67%

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Sen

Harrison

Burroughs

et al. 2021

Preprint

View full text Add to dashboard Cite

Chromosome mis-segregation during mitosis leads to daughter cells with deviant karyotypes (aneuploidy) and an increased mutational burden through chromothripsis of mis-segregated chromosomes. The rate of mis-segregation and the aneuploidy state are hallmarks of cancer and linked to cancer genome evolution. Errors can manifest as lagging chromosomes in anaphase, although the mechanistic origins and likelihood of correction are incompletely understood. Here we combine lattice light sheet microscopy, endogenous protein labelling and computational analysis to define the life history of >10^4 kinetochores throughout metaphase and anaphase from over 200 cells. By defining the laziness of kinetochores in anaphase, we reveal that chromosomes are at a considerable and continual risk of mis-segregation. We show that the majority of kinetochores are corrected rapidly in early anaphase through an Aurora B dependent process. Moreover, quantitative analyses of the kinetochore life histories reveal a unique dynamic signature of metaphase kinetochore oscillations that forecasts their fate in the subsequent anaphase. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with a new layer of early anaphase error correction required for stable karyotype propagation.

show abstract

Section: Discussionmentioning

confidence: 67%

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Sen

Harrison

Burroughs

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…However, in our live cell experiments, at the time resolution used, the kinetics of BAF and LBR recruitment to the nascent micronucleus were similar in lagging and in ensheathed chromosomes, and these were in turn comparable to NE recruitment at the main nucleus. Recent work has also countered the idea that spindle microtubules delay nuclear envelope recruitment at lagging chromosomes, in any case the NE is reformed by the end of mitosis (Orr et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Ferrándiz¹,

Downie²,

Starling

et al. 2021

Preprint

View full text Add to dashboard Cite

Errors in mitosis that cause chromosome missegregation lead to aneuploidy and micronuclei formation which are associated with cancer. Accurate segregation requires the alignment of all chromosomes by the mitotic spindle at the metaphase plate, and any misalignment must be corrected before anaphase is triggered. The spindle is situated in a membrane-free “exclusion zone”, beyond this zone, endomembranes (endoplasmic reticulum, nuclear envelope and other organelles) are densely packed. We asked what happens to misaligned chromosomes that find themselves beyond the exclusion zone? Here we show that such chromosomes become ensheathed in multiple layers of endomembranes. Chromosome ensheathing delays mitosis and increases the frequency of chromosome missegregation and subsequent micronuclei formation. We use an induced organelle relocalization strategy in live cells to show that clearance of endomembranes allows for the rescue of chromosomes that were destined for missegregation. Our findings indicate that endomembranes promote the missegregation of misaligned chromosomes that are outside the exclusion zone, and therefore constitute a novel pathway to aneuploidy.

show abstract

“…In summary, we have shown that phosphorylation driven by the Aurora B gradient helps sustain kinetochore structure over the time and distance necessary for normal anaphase chromosome segregation, and regulates kinetochore disassembly as cells enter telophase. This spatial regulation of kinetochore phosphorylation may also allow kinetochore stability on lagging chromosomes to be maintained to facilitate their movement to the poles in anaphase 52 .…”

Section: Discussionmentioning

confidence: 99%

The Aurora B gradient sustains kinetochore stability in anaphase

Papini

Levasseur

Higgins

2021

Preprint

View full text Add to dashboard Cite

Kinetochores assemble on chromosomes in mitosis to allow microtubules to attach and bring about accurate chromosome segregation. The kinases Cyclin B-Cdk1 and Aurora B are crucial for the formation of stable kinetochores. However, the activity of these two kinases appears to decline dramatically at centromeres during anaphase onset, precisely when microtubule attachments are required to move chromosomes towards opposite poles of the dividing cell. We find that, although Aurora B leaves centromeres at anaphase, a gradient of Aurora B activity centred on the central spindle is still able to phosphorylate kinetochore substrates such as Dsn1 to modulate kinetochore stability in anaphase and to regulate kinetochore disassembly as cells enter telophase. We provide a model to explain how Aurora B co-operates with Cyclin B-Cdk1 to maintain kinetochore function in anaphase.

show abstract

An anaphase surveillance mechanism prevents micronuclei formation from mitotic errors

Cited by 7 publications

References 73 publications

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

The Aurora B gradient sustains kinetochore stability in anaphase

Contact Info

Product

Resources

About