title: Escape from telomere-driven crisis is DNA ligase III dependent.
abstract: 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.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Rhiannon E
authors.initials: RE
authors.lastname: Jones
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Sehyun
authors.initials: S
authors.lastname: Oh
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Julia W
authors.initials: JW
authors.lastname: Grimstead
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Zimbric
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Laureline
authors.initials: L
authors.lastname: Roger
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Heppel
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Ashelford
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Liddiard
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic address: bairddm@cf.ac.uk.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
mesh_terms: D017209:Apoptosis; D020134:Catalytic Domain; D059766:DNA End-Joining Repair; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D011995:Recombination, Genetic; D059505:Telomere Homeostasis; D029867:Xenopus Proteins
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human