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The nature of telomere fusion and a definition of the critical telomere length in human cells
Open accessAbstract
The loss of telomere function can result in telomeric fusion events that lead to the types of genomic rearrangements, such as nonreciprocal translocations, that typify early-stage carcinogenesis. By using single-molecule approaches to characterize fusion events, we provide a functional definition of fusogenic telomeres in human cells. We show that approximately half of the fusion events contained no canonical telomere repeats at the fusion point; of those that did, the longest was 12.8 repeats. Furthermore, in addition to end-replication losses, human telomeres are subjected to large-scale deletion events that occur in the presence or absence of telomerase. Here we show that these telomeres are fusogenic, and thus despite the majority of telomeres being maintained at a stable length in normal human cells, a subset of stochastically shortened telomeres can potentially cause chromosomal instability. Telomere fusion was accompanied by the deletion of one or both telomeres extending several kilobases into the telomere-adjacent DNA, and microhomology was observed at the fusion points. This contrasted with telomere fusion that was observed following the experimental disruption of TRF2. The distinct error-prone mutational profile of fusion between critically shortened telomeres in human cells was reminiscent of Ku-independent microhomology-mediated end-joining.
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“The segmental aneuploidies identified by cytogenetics analysis (Figs. 1B and S3-S5) most probably point to the occurrence of complex genomic rearrangements in OCT4-targeted samples, such as chromosomal translocations or end-to-end fusions, as it seems unlikely that the rest of the chromosome would continue to be retained without a telomere (31)(32)(33).”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [33]
In the citing paper
“Telomere fusions formed during telomere crisis in cultured cells are mediated by alt-NHEJ and exhibit insertion of new sequences at the fusion point75,76.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [75]
In the citing paper
“Using this approach, evidence for past telomere crisis has been obtained in CLL as well as in breast cancer, colorectal adenomas and other solid tumours75,77,78.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [75]
In the citing paper
“Critical telomere shortening (12.8 repeats of repetitive clusters) either as a loss of telomere-capping proteins results to telomere dysfunction with consequent chromosomes fusion and genome instability [22].”
From Markers of cellular senescence. Telomere shortening as a marker of cellular senescence (2016) · cites this paper as [22]
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Cites
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Self-citation
Metadata
- Authors
- Capper, R., Britt-Compton, B., Tankimanova, M., Rowson, J., Letsolo, B., Man, S., Haughton, M., & Baird, D. M.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Baird, Duncan M.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-10-01
- Volume
- 21
- Issue
- 19
- Pages
- 2495-2508
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1993879
- OpenAlex
- W2159349156
- Cited by
- 294
- References
- 62
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 17 · 2023: 11 · 2022: 18 · 2021: 19 · 2020: 14 · 2019: 8 · 2018: 22 · 2017: 21 · 2016: 16 · 2015: 19 · 2014: 14 · 2013: 13 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- Cancer Research UK
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- telomere fusion, telomere shortening, chromosomal instability, non-reciprocal translocation, microhomology-mediated end joining, TRF2, telomerase, carcinogenesis, single-molecule analysis
- MeSH terms
- Base Sequence, Humans, Molecular Sequence Data, Mutagenesis, Insertional, Telomere, Cellular Senescence, Sequence Deletion, Tandem Repeat Sequences, Telomeric Repeat Binding Protein 2, Chromosomal Instability, Cell Line, Tumor
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