Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

Sen, Onur; Harrison, Jonathan U.; Burroughs, Nigel John; McAinsh, Andrew D.

doi:10.1016/j.devcel.2021.11.023

Cited by 12 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Near-complete tracking of kinetochores through metaphase–anaphase transition in human RPE1 cells. ( A ) Sequence of images [as in Sen et al (2021) ] showing metaphase–anaphase transition with dragontails indicating tracked and paired kinetochores. Magenta (cyan) lines show trajectories over the next (previous) five frames.…”

Section: Resultsmentioning

confidence: 99%

Kinetochore tracking in 3D from lattice light-sheet imaging data with KiT

et al. 2022

Self Cite

View full text Add to dashboard Cite

Motivation Lattice light sheet microscopy is revolutionizing cell biology since it enables fast, high-resolution extended imaging in three dimensions combined with a drastic reduction in photo-toxicity and bleaching. However analysis of such data sets still remains a major challenge. Results Automated tracking of kinetochores, the protein complex facilitating and controlling microtubule attachment of the chromosomes within the mitotic spindle, provides quantitative assessment of chromosome dynamics in mitosis. Here we extend existing open-source kinetochore tracking software (KiT Armond et al. [2016]) to track (and pair) kinetochores throughout pro-metaphase to anaphase in lattice light sheet microscopy data. One of the key improvements is a regularization term in the objective function to enforce biological information about the number of kinetochores in a human mitotic cell, as well as improved diagnostic tools. This software provides quantitative insights into how kinetochores robustly ensure congression and segregation of chromosomes during mitosis. Availability and implementation KiT is free, open-source software implemented in MATLAB and can be downloaded as a package from https://github.com/cmcb-warwick/KiT. The source repository is available at https://bitbucket.org/jarmond/kit (tag v2.4.0) and under continuing development. Supplementary information Supplementary data are available at Bioinformatics online.

show abstract

Section: Resultsmentioning

confidence: 99%

Kinetochore tracking in 3D from lattice light-sheet imaging data with KiT

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…One possibility supported by our data is that Aurora A activity is not altered in the case of long-term DNA damage in cells delayed in mitosis for several hours. Because most anaphase lagging chromosomes in normal and cancer cells rarely form micronuclei and were recently shown to be actively corrected by an anaphase surveillance mechanism involving Aurora B activity at the spindle midzone (Orr et al, 2021; Sen et al, 2021), the presence of misaligned chromosomes that eventually satisfy the SAC upon long-term DNA damage might represent a higher risk for micronuclei formation and consequent genomic instability due to chromothripsis. Indeed, we recently found that systematic perturbation of kinetochore-microtubule attachments caused human cancer cells to enter anaphase after a delay with chronically misaligned chromosomes that eventually satisfy the SAC and missegregate, leading to the formation of micronuclei (Gomes et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Long-term mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells

Novais-Cruz

Pombinho

Sousa

et al. 2022

Preprint

View full text Add to dashboard Cite

DNA damage response (DDR) during interphase involves active signalling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage remains poorly understood. Supported by correlative live-/fixed-cell microscopy analysis we found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon long-term DNA damage during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but DDR-independent, mitotic delay. This delay was due to the presence of misaligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, we show that long-term mitotic DNA damage specifically stabilizes kinetochore-microtubule attachments in cancer cells, causing the missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Overall, these findings unveil that long-term therapeutic DNA damage regimens contribute to genomic instability through a surprising link between the stabilization of kinetochore-microtubule attachments and chromokinesin-mediated missegregation of polar chromosomes in cancer cells.

show abstract

“…Recent high-resolution live-cell studies tracking kinetochore or chromosome behavior through metaphase and anaphase in human somatic cells in culture have revealed that many more chromosomes tend to lag behind in anaphase than previously anticipated ( Orr et al, 2021 ; Sen et al, 2021 ). This behavior is, at least in part, due to prevailing merotelic attachments and can be predicted from their oscillatory pattern during metaphase ( Cimini et al, 2004 ; Sen et al, 2021 ). Importantly, most laggards have a transient nature and resume poleward motion, suggesting an active error correction mechanism that prevents missegregation.…”

Section: Mechanism Of Anaphase Error Correctionmentioning

confidence: 92%

Double-checking chromosome segregation

Maiato

Silva

2023

Journal of Cell Biology

View full text Add to dashboard Cite

Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei—key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore–microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability.

show abstract

Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

Abstract: instead of as the actual November 9, 2021, publication date. This error has now been corrected in the online PDF version of the article. We regret this error and apologize for any confusion that it may have caused.

Cited by 12 publications

References 0 publications

Kinetochore tracking in 3D from lattice light-sheet imaging data with KiT

Kinetochore tracking in 3D from lattice light-sheet imaging data with KiT

Long-term mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells

Double-checking chromosome segregation

Contact Info

Product

Resources

About