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Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response
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 rearrange...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787266/ https://www.ncbi.nlm.nih.gov/pubmed/33447828 http://dx.doi.org/10.1093/narcan/zcaa044 |
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author | Liddiard, Kate Grimstead, Julia W Cleal, Kez Evans, Anna Baird, Duncan M |
author_facet | Liddiard, Kate Grimstead, Julia W Cleal, Kez Evans, Anna Baird, Duncan M |
author_sort | Liddiard, Kate |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7787266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77872662021-01-12 Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response Liddiard, Kate Grimstead, Julia W Cleal, Kez Evans, Anna Baird, Duncan M NAR Cancer DNA Damage Sensing and Repair 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. Oxford University Press 2021-01-06 /pmc/articles/PMC7787266/ /pubmed/33447828 http://dx.doi.org/10.1093/narcan/zcaa044 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | DNA Damage Sensing and Repair Liddiard, Kate Grimstead, Julia W Cleal, Kez Evans, Anna Baird, Duncan M Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title | Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title_full | Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title_fullStr | Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title_full_unstemmed | Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title_short | Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response |
title_sort | tracking telomere fusions through crisis reveals conflict between dna transcription and the dna damage response |
topic | DNA Damage Sensing and Repair |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787266/ https://www.ncbi.nlm.nih.gov/pubmed/33447828 http://dx.doi.org/10.1093/narcan/zcaa044 |
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