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

Kate Liddiard, Brian Ruis, Yinan Kan, Kez Cleal, Kevin E. Ashelford, Eric A. Hendrickson, Duncan M. Baird

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 nonhomologous end-joining uniquely position and ca-pacitate this ligase for DNA repair at stalled replication forks, facilitating mitotic progression.

Original languageEnglish (US)
Pages (from-to)2402-2424
Number of pages23
JournalNucleic acids research
Volume47
Issue number5
DOIs
StatePublished - Mar 18 2019

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