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Modest increase of KIF11 exposes fragilities in the mitotic spindle causing chromosomal instability

Dale, Katie L; Armond, Jonathan W; Hynds, Robert E; Vladimirou, Elina; (2022) Modest increase of KIF11 exposes fragilities in the mitotic spindle causing chromosomal instability. Journal of Cell Science , 135 (17) , Article jcs.260031. 10.1242/jcs.260031. Green open access

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Abstract

Chromosomal instability (CIN), the process of increased chromosomal alterations, compromises genomic integrity and has profound consequences on human health. Yet, our understanding of the molecular and mechanistic basis of CIN initiation remains limited. We developed a high-throughput, single-cell image-based pipeline employing deep learning and spot counting models to detect CIN by automatically counting chromosomes and micronuclei. To identify CIN-initiating conditions, we used CRISPR activation in human diploid cells to upregulate, at physiologically-relevant levels, 14 genes that are functionally important in cancer. We found that upregulation of CCND1, FOXA1, and NEK2 resulted in pronounced changes in chromosome counts and KIF11 upregulation resulted in micronuclei formation. We identified KIF11-dependent fragilities within the mitotic spindle; increased KIF11 causes centrosome fragmentation, higher microtubule stability, lagging chromosomes or mitotic catastrophe. Our findings demonstrate that even modest average single gene expression changes in a karyotypically stable background are sufficient for initiating CIN by exposing fragilities of the mitotic spindle which can lead to a genomically-diverse cell population.

Type: Article
Title: Modest increase of KIF11 exposes fragilities in the mitotic spindle causing chromosomal instability
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.260031
Publisher version: https://doi.org/10.1242/jcs.260031
Language: English
Additional information: © 2022. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: CRISPR activation, Chromosomal instability, Confocal imaging, Deep learning, KIF11, Mitosis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10153569
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