eprintid: 10153569
rev_number: 15
eprint_status: archive
userid: 699
dir: disk0/10/15/35/69
datestamp: 2022-08-11 11:17:26
lastmod: 2022-10-14 16:25:40
status_changed: 2022-08-11 11:17:26
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Dale, Katie L
creators_name: Armond, Jonathan W
creators_name: Hynds, Robert E
creators_name: Vladimirou, Elina
title: Modest increase of KIF11 exposes fragilities in the mitotic spindle causing chromosomal instability
ispublished: pub
divisions: C10
divisions: G99
divisions: B02
divisions: UCL
divisions: D19
keywords: CRISPR activation, Chromosomal instability, Confocal imaging, Deep learning, KIF11, Mitosis
note: © 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.
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.
date: 2022-09
date_type: published
publisher: The Company of Biologists
official_url: https://doi.org/10.1242/jcs.260031
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1969394
doi: 10.1242/jcs.260031
medium: Print-Electronic
pii: 276220
lyricists_name: Hynds, Robert
lyricists_id: HYNDS02
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
funding_acknowledgements: C7893/A24956 [Cancer Research UK]; WT209199/Z/17/Z [Wellcome Trust]; [NIHR Great Ormond Street Hospital Biomedical Research Centre]
full_text_status: public
publication: Journal of Cell Science
volume: 135
number: 17
article_number: jcs.260031
event_location: England
citation:        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 <https://doi.org/10.1242/jcs.260031>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10153569/1/DownloadCombinedArticleAndSupplmentPdf.pdf