Replication stress causes delayed mitotic entry and chromosome 12 fragility at the ANKS1B large neuronal gene in human induced pluripotent stem cells.
ANKS1B
Aphidicolin
Common fragile sites
FRA12L
Induced pluripotent stem cells
Replication stress
Journal
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology
ISSN: 1573-6849
Titre abrégé: Chromosome Res
Pays: Netherlands
ID NLM: 9313452
Informations de publication
Date de publication:
19 08 2023
19 08 2023
Historique:
received:
05
04
2023
accepted:
19
07
2023
revised:
10
07
2023
medline:
21
8
2023
pubmed:
19
8
2023
entrez:
19
8
2023
Statut:
epublish
Résumé
Substantial background level of replication stress is a feature of embryonic and induced pluripotent stem cells (iPSCs), which can predispose to numerical and structural chromosomal instability, including recurrent aberrations of chromosome 12. In differentiated cells, replication stress-sensitive genomic regions, including common fragile sites, are widely mapped through mitotic chromosome break induction by mild aphidicolin treatment, an inhibitor of replicative polymerases. IPSCs exhibit lower apoptotic threshold and higher repair capacity hindering fragile site mapping. Caffeine potentiates genotoxic effects and abrogates G2/M checkpoint delay induced by chemical and physical mutagens. Using 5-ethynyl-2'-deoxyuridine (EdU) for replication labeling, we characterized the mitotic entry dynamics of asynchronous iPSCs exposed to aphidicolin and/or caffeine. Under the adjusted timing of replication stress exposure accounting revealed cell cycle delay, higher metaphase chromosome breakage rate was observed in iPSCs compared to primary lymphocytes. Using differential chromosome staining and subsequent locus-specific fluorescent in situ hybridization, we mapped the FRA12L fragile site spanning the large neuronal ANKS1B gene at 12q23.1, which may contribute to recurrent chromosome 12 missegregation and rearrangements in iPSCs. Publicly available data on the ANKS1B genetic alterations and their possible functional impact are reviewed. Our study provides the first evidence of common fragile site induction in iPSCs and reveals potential somatic instability of a clinically relevant gene during early human development and in vitro cell expansion.
Identifiants
pubmed: 37597021
doi: 10.1007/s10577-023-09729-5
pii: 10.1007/s10577-023-09729-5
doi:
Substances chimiques
Aphidicolin
38966-21-1
Caffeine
3G6A5W338E
ANKS1B protein, human
0
Intracellular Signaling Peptides and Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature B.V.
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