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

Area of Science:

• Genomics
• Cancer Biology
• Molecular Biology

Background:

• Telomere dysfunction is a hallmark of cancer, driving genomic instability.
• The precise mechanisms and consequences of telomere-driven replicative crisis on genome architecture are not fully understood.
• Novel biomarkers for cellular stress in cancer progression remain to be discovered.

Purpose of the Study:

• To investigate the genomic and architectural changes during telomere-driven replicative crisis.
• To identify potential biomarkers associated with cellular stress and cancer progression.

Main Methods:

• High-resolution multi-omics analyses in a human fibroblast model of crisis.
• Development of a novel chromatin conformation capture procedure to study telomere interactions.
• Targeted capture panel and short/long-read sequencing for repetitive and extrachromosomal DNA analysis.

Main Results:

• Identified large-scale structural genomic changes and a shift from local to distant genomic interactions during crisis.
• Revealed crisis-induced chromatin decompaction, altered gene expression, and ageing signatures in centromeric sequences.
• Observed significant transitions in extrachromosomal circular DNA (eccDNA) abundance, complexity, and sequence content during crisis.

Conclusions:

• Telomere dysfunction and transcription-driven chromatin reorganization link replication stress to genome instability.
• These processes facilitate telomere fusions, eccDNA emergence, and overall genomic instability.
• The identified changes represent dynamic biomarkers of cellular stress relevant to cancer progression.