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

Liddiard, Kate, Ruis, Brian, Takasugi, Taylor, Harvey, Adam, Ashelford, Kevin E., Hendrickson, Eric and Baird, Duncan 2016. Sister chromatid, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4. Genome Research 26 (5) , pp. 588-600. 10.1101/gr.200840.115

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Abstract

Telomeres shorten with each cell division and can ultimately become substrates for non-homologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterised over 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 non-telomeric 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, non-homologous 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 an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Additional Information: This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
Publisher: Cold Spring Harbor Laboratory Press
ISSN: 1088-9051
Funders: Cancer Research UK, National Institutes of Health, National Cancer Institute
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 2 March 2016
Last Modified: 23 May 2019 05:04
URI: http://orca.cf.ac.uk/id/eprint/87500

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