The nature of telomere fusion and a definition of the critical telomere length in human cells

Capper, Rebecca, Britt-Compton, Bethan, Tankimanova, Maira, Rowson, Janet Maud, Letsolo, Boitelo, Man, Stephen Tzekwung ORCID: https://orcid.org/0000-0001-9103-1686, Haughton, Michele Fleur and Baird, Duncan Martin ORCID: https://orcid.org/0000-0001-8408-5467 2007. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes and Development 21 (19) , pp. 2495-2508. 10.1101/gad.439107

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Telomere ; telomerase ; genomic instability ; mutation ; DNA repair ; neoplasia
ISSN:	0890-9369
Date of First Compliant Deposit:	30 March 2016
Last Modified:	01 Nov 2023 07:35
URI:	https://orca.cardiff.ac.uk/id/eprint/164

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