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Escape from telomere-driven crisis is DNA ligase III dependent.

Authors
  • Jones, Rhiannon E1
  • Oh, Sehyun2
  • Grimstead, Julia W1
  • Zimbric, Jacob2
  • Roger, Laureline1
  • Heppel, Nicole H1
  • Ashelford, Kevin E1
  • Liddiard, Kate1
  • Hendrickson, Eric A2
  • Baird, Duncan M3
  • 1 Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • 2 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  • 3 Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Aug 21, 2014
Volume
8
Issue
4
Pages
1063–1076
Identifiers
DOI: 10.1016/j.celrep.2014.07.007
PMID: 25127141
Source
Medline
Language
English
License
Unknown

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. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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