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.
Highlights
The finite proliferative capacity of human primary fibroblasts was first documented by Hayflick and Moorhead in 1961 [1] and attributed to intrinsic factors that resulted in a state of cellular senescence
Progression through telomere crisis is accompanied by transitions in DNA repair We previously observed an elevated frequency of coding sequences incorporated into telomere fusions compared with intergenic loci [27,28]
The advance through crisis was delineated by progressive incidence of telomere fusions amplified with chr17p, chr21q and chrXpYp subtelomere-specific primers [19,21,32] for all E6E7-transformed fibroblasts (Figure 1Aii and B), but rarely from the neomycinresistance alone (NEO) controls (Supplementary Figure S1C)
Summary
The finite proliferative capacity of human primary fibroblasts was first documented by Hayflick and Moorhead in 1961 [1] and attributed to intrinsic factors that resulted in a state of cellular senescence. The characteristic irreversible senescent growth arrest can be triggered by telomere attrition to a length at which chromosome ends are exposed as double-stranded DNA breaks (DSB) [2], activating RB1 and TP53 tumour suppressor cell cycle checkpoints [3]. Morphological changes [6] that culminate in the secretion of inflammatory mediators and growth factors as part of the senescence-associated secretory phenotype (SASP) [7]. More comprehensive appreciation of the multitudinous signalling pathways [10] that contribute to the pro-inflammatory capacity and apoptotic resistance of senescent cells would undoubtedly expedite viable therapeutic approaches [11,12]
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