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.[Keywords: Telomere; telomerase; genomic instability; mutation; DNA repair; neoplasia] Supplemental material is available at http://www.genesdev.org.

Human Rap1 Interacts Directly with Telomeric DNA and Regulates TRF2 Localization at the Telomere

“…On long telomeres, the TRF2-Rap1 complex could initiate t-loop formation and prevent DDR or as the telomere length becomes shorter (to a level where the t-loops cannot be formed) then with its very high affinity for the 3Ј ds-ss telomeric end, the TRF2-Rap1 complex could suppress the unnecessary DDR by blocking the end and making it less accessible to DNA repair proteins. Indeed, the finding that very short telomeres without t-loops exist stably in vivo (47), that the TRF2-Rap1 complex can prevent NHEJ of telomeres with less than 10 repeats and in the absence of Rap1, can only be compensated by significantly high amounts of hTRF2 to facilitate end protection (12,48) provide support to this model. Depending on what parameter one measures, the loss of Rap1 in cells may be considered to be important for end protection or not (12,28).…”

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

“…It is also known that the shortest telomere, not average telomere length, is critical for cell viability and chromosome stability (73). When the number of telomeric repeats falls below 13, chromosomal instability is observed (74). At the time of integration, the TMR in DR L contains approximately 50 to 60 repeats (23,75).…”

Telomere dysfunction and tumour suppression: the senescence connection

“…One important cytogenetic distinction between these two repair processes is that the fusion points of chromosomes with naturally shortened telomeres do not normally posses FISH-detectable telomeric DNA, while fused chromosomes resulting from loss of shelterin components frequently posses intense telomeric signals at the sites of fusion. While NHEJ and HR pathways account for the vast majority of chromosomal fusions, other pathways of repair such as microhomology mediated telomere-telomere recombination may also be involved, especially when the classic repair pathways are compromised [18][19][20] .…”