title: The nature of telomere fusion and a definition of the critical telomere length in human cells.
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.
authors.affiliation: Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Capper
authors.forename: Bethan
authors.initials: B
authors.lastname: Britt-Compton
authors.forename: Maira
authors.initials: M
authors.lastname: Tankimanova
authors.forename: Jan
authors.initials: J
authors.lastname: Rowson
authors.forename: Boitelo
authors.initials: B
authors.lastname: Letsolo
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.forename: Michele
authors.initials: M
authors.lastname: Haughton
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D017384:Sequence Deletion; D020080:Tandem Repeat Sequences; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics
chemical_list: D035341:Telomeric Repeat Binding Protein 2