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DNA Ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase

Liddiard, Kate, Ruis, Brian, Kan, Yinan, Cleal, Kez, Ashelford, Kevin E, Hendrickson, Eric A and Baird, Duncan M 2018. DNA Ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase. Nucleic Acids Research 47 (5) , pp. 2402-2424. 10.1093/nar/gky1279

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Abstract

Fusion of critically short or damaged telomeres is associated with the genomic rearrangements that support malignant transformation. We have demonstrated the fundamental contribution of DNA ligase 4-dependent classical non-homologous end-joining to long-range inter-chromosomal telomere fusions. In contrast, localized genomic recombinations initiated by sister chromatid fusion are predominantly mediated by alternative non-homologous end-joining activity that may employ either DNA ligase 3 or DNA ligase 1. In this study, we sought to discriminate the relative involvement of these ligases in sister chromatid telomere fusion through a precise genetic dissociation of functional activity. We have resolved an essential and non-redundant role for DNA ligase 1 in the fusion of sister chromatids bearing targeted double strand DNA breaks that is entirely uncoupled from its requisite engagement in DNA replication. Importantly, this fusogenic repair occurs in cells fully proficient for non-homologous end-joining and is not compensated by DNA ligases 3 or 4. The dual functions of DNA ligase 1 in replication and non-homologous end-joining uniquely position and capacitate this ligase for DNA repair at stalled replication forks, facilitating mitotic progression.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Oxford University Press (OUP): Policy C - Option B / Oxford University Press
ISSN: 0305-1048
Funders: Cancer Research UK
Date of First Compliant Deposit: 10 January 2019
Date of Acceptance: 14 December 2018
Last Modified: 30 Apr 2019 16:40
URI: http://orca.cf.ac.uk/id/eprint/118274

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