Tracking telomere fusions through crisis reveals tractable genomic vulnerabilities associated with the senescence transcriptome

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 transitions that characterise the evolution from active proliferation into terminal senescence. Progression through crisis was associated with recombination of asymmetric sister chromatid telomeres fused by alternative non-homologous end-joining. Eroded telomeres also fused with genomic loci engaged in dynamic transcription, with particular enrichment in long genes subject to replication stress in rapidly-dividing cells. Clusters of genomic vulnerabilities were conceivably underpinned by copy number alterations in concert with coordinated reprogramming of gene expression to engineer the cellular transformation into senescence. This study exposed a critical role for calcium signalling through NFAT (Nuclear factor of activated T-cells) transcription factors in directing the transcriptional stress response that governs the genomic rearrangements that support malignancy, cell death or senescence.