Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA Damage Response

Liddiard, Kate ORCID: https://orcid.org/0000-0002-0953-1997, Grimstead, Julia, Cleal, Kez, Evans, Anna and Baird, Duncan ORCID: https://orcid.org/0000-0001-8408-5467 2021. Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA Damage Response. NAR Cancer 3 (1) , zcaa044. 10.1093/narcan/zcaa044

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Abstract

Identifying attributes that distinguish pre-malignant from senescent cells provides opportunities for targeted disease eradication and revival of anti-tumour immunity. We modelled a telomere-driven crisis in four human fibroblast lines, sampling at multiple time points to delineate genomic rearrangements and transcriptome developments that characterize the transition from dynamic proliferation into replicative crisis. Progression through crisis was associated with abundant intra-chromosomal telomere fusions with increasing asymmetry and reduced microhomology usage, suggesting shifts in DNA repair capacity. Eroded telomeres also fused with genomic loci actively engaged in transcription, with particular enrichment in long genes. Both gross copy number alterations and transcriptional responses to crisis likely underpin the elevated frequencies of telomere fusion with chromosomes 9, 16, 17, 19 and most exceptionally, chromosome 12. Juxtaposition of crisis-regulated genes with loci undergoing de novo recombination exposes the collusive contributions of cellular stress responses to the evolving cancer genome.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	2632-8674
Funders:	CRUK
Date of First Compliant Deposit:	18 December 2020
Date of Acceptance:	17 December 2020
Last Modified:	27 Oct 2023 06:20
URI:	https://orca.cardiff.ac.uk/id/eprint/137117

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