Investigating the mechanistic basis of telomeric fusions

Furthermore, NBS1 deficiency results in a paucity of sporadic telomere deletion events which is consistent with the hypothesis that NBS1 is involved in the resolution of Holiday junctions within T-loops creating telomeric deletion events. In contrast, DNA Ligase IV deficiency and PARP1 inhibition caused distinct short telomere length distributions. Both these phenotypes might be related to problems with telomere replication.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigating the mechanistic basis of telomeric fusions

Furthermore, NBS1 deficiency results in a paucity of sporadic telomere deletion events which is consistent with the hypothesis that NBS1 is involved in the resolution of Holiday junctions within T-loops creating telomeric deletion events. In contrast, DNA Ligase IV deficiency and PARP1 inhibition caused distinct short telomere length distributions. Both these phenotypes might be related to problems with telomere replication.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigating the mechanistic basis of telomeric fusions

Furthermore, NBS1 deficiency results in a paucity of sporadic telomere deletion events which is consistent with the hypothesis that NBS1 is involved in the resolution of Holiday junctions within T-loops creating telomeric deletion events. In contrast, DNA Ligase IV deficiency and PARP1 inhibition caused distinct short telomere length distributions. Both these phenotypes might be related to problems with telomere replication

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL

Escape from Telomere-Driven Crisis Is DNA Ligase III Dependent

Short dysfunctional telomeres are capable of fusion, generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. Cells that escape the ensuing cellular crisis exhibit large-scale genomic rearrangements that drive clonal evolution and malignant progression. We demonstrate that there is an absolute requirement for fully functional DNA ligase III (LIG3), but not ligase IV (LIG4), to facilitate the escape from a telomere-driven crisis. LIG3- and LIG4-dependent alternative (A) and classical (C) nonhomologous end-joining (NHEJ) pathways were capable of mediating the fusion of short dysfunctional telomeres, both displaying characteristic patterns of microhomology and deletion. Cells that failed to escape crisis exhibited increased proportions of C-NHEJ-mediated interchromosomal fusions, whereas those that escaped displayed increased proportions of intrachromosomal fusions. We propose that the balance between inter- and intrachromosomal telomere fusions dictates the ability of human cells to escape crisis and is influenced by the relative activities of A- and C-NHEJ at short dysfunctional telomeres