Structural stability and chromosome-specific telomere length is governed by cis-acting determinants in humans

Abstract

Single telomere length analysis (STELA) of the XpYp telomere has revealed extensive allelic variation and ultra-short telomeres in senescent cells. Superimposed on end-replication losses are additional mutational events that result in large-scale changes in telomere length. In order to establish if the dynamics of the XpYp telomere are typical of human telomeres, here we describe an analysis using STELA of the telomeres of 2p, 11q, 12q, 17p and XpYp. The dynamics of telomere loss (erosion rates and stochastic length changes) was conserved among 2p, 11q, 12q and XpYp within the same cell strains and was dependent on the replicative kinetics of the cells in culture. However, of the telomeres analysed, the telomere of 17p was more stable with a striking paucity of large-scale length changes, and exhibited the shortest recorded allelic distribution (300 bp) in senescent cells and displayed a general, but not absolute, trend towards being the shortest telomere. Ectopic over-expression of hTERT homogenized both allelic and chromosome-specific telomeric distributions. However, telomerase-expressing cancer cells displayed both allelic variation and chromosome-specific telomere length, with 17p displaying the shortest allelic telomere length. Although other telomeres in the genome may share the properties of 17p, these data suggest that physiological levels of telomerase allow differential telomere length regulation and indicate the presence of cis-acting factors that govern both telomeric stability and chromosome-specific telomere length in the presence of telomerase.

Longer Relative Telomere Length in Blood from Women with Sporadic and Familial Breast Cancer Compared with Healthy Controls

“…Individual chromosome telomere length may more accurately predict cellular survival than average telomere length, and some studies have linked cancer risk to specific telomere length, albeit only with regard to shortening (47)(48)(49). Single telomere length analysis with quantitative PCR is limited by the generation of complex subtelomeric chromosome specific primers and, to date, is only available for chromosomes 2p, 11q, 12q, 17p, Xp, and Yp (50,51). Given that our findings suggest longer RTL in High-and Low-Risk Case populations, and current evidence does not support biological effect of a lengthened single chromosome telomere, this analysis was not explored.…”

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

“…Telomere fusion amplicons were generated from sample input genomic DNA (50 ng from HCT116 or 12.5 ng from the MRC5 HPVE6E7 cell line) by multiplex long-range PCR using primers targeting the 17p, XpYp, and 21q family of homologous telomeres (17p6, XpYpM, and 21q1 primers, respectively) (Britt-Compton et al 2006;Letsolo et al 2010). This resulted in mixed pools of fusion amplicons with divergent molecular weights.…”

Telomere dysfunction and its role in haematological cancer

“…This was addressed by Lin et al (2010), who made use of the STELA technique, which allows for the measurement of very short telomeres (Baird et al, 2003;Britt-Compton et al, 2006), including those which lose their end capping function and are subject to fusion (Capper et al, 2007); telomeres of these lengths are not represented in the other methods of measuring TL including TRF analysis, Q-PCR and quantitative FISH. An accompanying single molecule telomere fusion assay was also used, which allowed the DNA sequence of single telomere fusion events to be characterized (Capper et al, 2007;Letsolo et al, 2010).…”