RT Journal Article
SR Electronic
T1 Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.30.436326
DO 10.1101/2021.03.30.436326
A1 Onur Sen
A1 Jonathan U. Harrison
A1 Nigel J. Burroughs
A1 Andrew D. McAinsh
YR 2021
UL http://biorxiv.org/content/early/2021/03/31/2021.03.30.436326.abstract
AB 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 > 104 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.Competing Interest StatementThe authors have declared no competing interest.