title: Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4.
abstract: Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 double-knockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom;
authors.forename: Kate
authors.initials: K
authors.lastname: Liddiard
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruis
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Takasugi
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom;
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Ashelford
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 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, United Kingdom;
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
mesh_terms: D045744:Cell Line, Tumor; D002842:Chromatids / Q000235:genetics / Q000378:metabolism; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D000072481:DNA Ligase ATP; D017353:Gene Deletion; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53
chemical_list: C000607893:LIG4 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000072481:DNA Ligase ATP