Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Inactivation of RB1, CDKN2A and TP53 have distinct effects on genomic stability at side-by-side comparison in karyotypically normal cells

Andersson, Natalie LU orcid ; Saba, Karim LU orcid ; Magnusson, Linda LU ; Nilsson, Jenny LU ; Karlsson, Jenny LU ; Hansén Nord, Karolin LU and Gisselsson Nord, David LU (2023) In Genes, Chromosomes and Cancer 62(2). p.93-100
Abstract
Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side-by-side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR-Cas9 technology, RB1, CDKN2A and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all... (More)
Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side-by-side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR-Cas9 technology, RB1, CDKN2A and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all three knockouts. Surprisingly, the RB1 and CDKN2A knocked out cell lines did not harbor more copy number aberrations than wild-type cells, despite culturing for months. The TP53-knocked out cells, in contrast, showed a massive amount of copy number alterations and saltatory evolution through whole genome duplication. This side-by-side comparison indicated that the effects on chromosomal stability from inactivation of RB1 and CDKN2A are negligible compared to inactivation of TP53, under the same conditions in a non-stressful environment, even though partly overlapping regulatory pathways are affected. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genes, Chromosomes and Cancer
volume
62
issue
2
pages
93 - 100
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:36124964
  • scopus:85138926936
ISSN
1045-2257
DOI
10.1002/gcc.23096
language
English
LU publication?
yes
id
88506b83-e81b-4506-b7f7-aecf915699ba
date added to LUP
2022-09-23 18:04:39
date last changed
2023-01-16 10:17:56
@article{88506b83-e81b-4506-b7f7-aecf915699ba,
  abstract     = {{Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side-by-side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR-Cas9 technology, RB1, CDKN2A and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all three knockouts. Surprisingly, the RB1 and CDKN2A knocked out cell lines did not harbor more copy number aberrations than wild-type cells, despite culturing for months. The TP53-knocked out cells, in contrast, showed a massive amount of copy number alterations and saltatory evolution through whole genome duplication. This side-by-side comparison indicated that the effects on chromosomal stability from inactivation of RB1 and CDKN2A are negligible compared to inactivation of TP53, under the same conditions in a non-stressful environment, even though partly overlapping regulatory pathways are affected.}},
  author       = {{Andersson, Natalie and Saba, Karim and Magnusson, Linda and Nilsson, Jenny and Karlsson, Jenny and Hansén Nord, Karolin and Gisselsson Nord, David}},
  issn         = {{1045-2257}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{93--100}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Genes, Chromosomes and Cancer}},
  title        = {{Inactivation of RB1, CDKN2A and TP53 have distinct effects on genomic stability at side-by-side comparison in karyotypically normal cells}},
  url          = {{http://dx.doi.org/10.1002/gcc.23096}},
  doi          = {{10.1002/gcc.23096}},
  volume       = {{62}},
  year         = {{2023}},
}