Telomere-driven replicative crisis is driven by large-scale changes in genomic architecture

Liddiard, Kate ORCID: https://orcid.org/0000-0002-0953-1997, Coral, Emmon, Bhatt, Harsh, Cleal, Kez and Baird, Duncan ORCID: https://orcid.org/0000-0001-8408-5467 2026. Telomere-driven replicative crisis is driven by large-scale changes in genomic architecture. Genome Research 36 (8) , pp. 1529-1547. 10.1101/gr.281373.125

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Abstract

Telomere-driven replicative crisis transforms the architecture of the evolving cancer genome, yet the mechanisms and consequences remain incompletely resolved, with potential biomarkers undiscovered. To address this, we have employed novel tools and methodologies to explore a human fibroblast model of crisis using high-resolution multiomic analyses. We have developed a unique chromatin conformation capture procedure for identifying distant genomic loci that interact with eroding telomeres, uncovering large-scale structural changes that accompany crisis transition. We reveal the remarkable shift from local to distant genomic interactions consistent with crisis-induced chromatin decompaction and altered gene expression. To resolve variation within challenging repetitive sequences disclosed in the complete telomere-to-telomere human reference, we have designed a targeted capture panel, uncovering aging signatures within centromeric sequences and gross copy number losses within ribosomal DNA tracks and near to the chromosome ends. We have employed both short- and long-read sequencing of purified extrachromosomal circular DNA to expose an unequivocal transition in the abundance, complexity, and sequence content of these sporadic structural variants during crisis. By integrating parallel sequencing data sets, we provide a multifaceted characterization of replicative crisis in unprecedented detail. Our findings demonstrate that telomere dysfunction and transcription-driven chromatin reorganization combine to connect replication stress to telomere fusions, eccDNA emergence and genome instability, generating dynamic biomarkers of cellular stress relevant to cancer progression.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Cold Spring Harbor Laboratory Press
ISSN:	1088-9051
Funders:	Cancer Research UK
Projects:	C17199/A29202
Date of First Compliant Deposit:	9 July 2026
Date of Acceptance:	22 June 2026
Last Modified:	30 Sep 2026 10:21
URI:	https://orca.cardiff.ac.uk/id/eprint/188110

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