Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining

Breakpoint junctions of the chromosomal translocations that occur in human cancers display hallmarks of nonhomologous end-joining (NHEJ). In mouse cells, translocations are suppressed by canonical NHEJ (c-NHEJ) components, which include DNA ligase IV (LIG4), and instead arise from alternative NHEJ (...

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Published in:Molecular cell 2014-09, Vol.55 (6), p.829-842
Main Authors: Ghezraoui, Hind, Piganeau, Marion, Renouf, Benjamin, Renaud, Jean-Baptiste, Sallmyr, Annahita, Ruis, Brian, Oh, Sehyun, Tomkinson, Alan E., Hendrickson, Eric A., Giovannangeli, Carine, Jasin, Maria, Brunet, Erika
Format: Article
Language:English
Subjects:
Animals
Chromosomes, Human
Deoxyribonucleases - physiology
DNA End-Joining Repair
DNA Ligase ATP
DNA Ligases - genetics
DNA-Binding Proteins - genetics
Humans
Mice
Sequence Deletion
Species Specificity
Translocation, Genetic - genetics
Tumor Cells, Cultured
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Summary:Breakpoint junctions of the chromosomal translocations that occur in human cancers display hallmarks of nonhomologous end-joining (NHEJ). In mouse cells, translocations are suppressed by canonical NHEJ (c-NHEJ) components, which include DNA ligase IV (LIG4), and instead arise from alternative NHEJ (alt-NHEJ). Here we used designer nucleases (ZFNs, TALENs, and CRISPR/Cas9) to introduce DSBs on two chromosomes to study translocation joining mechanisms in human cells. Remarkably, translocations were altered in cells deficient for LIG4 or its interacting protein XRCC4. Translocation junctions had significantly longer deletions and more microhomology, indicative of alt-NHEJ. Thus, unlike mouse cells, translocations in human cells are generated by c-NHEJ. Human cancer translocations induced by paired Cas9 nicks also showed a dependence on c-NHEJ, despite having distinct joining characteristics. These results demonstrate an unexpected and striking species-specific difference for common genomic rearrangements associated with tumorigenesis. [Display omitted] •Chromosomal translocations in human cells rely on canonical NHEJ (c-NHEJ)•ZFN-, TALEN-, and Cas9-induced junctions are altered in LIG4-XRCC4 mutant human cells•Cas9 DSB- and paired nick-induced oncogenic translocations have distinct junctions Ghezraoui et al. use designer nucleases (ZFNs, TALENs, CRISPR/Cas9, and nCas9) to introduce concurrent double-strand breaks on two chromosomes to study chromosomal translocation joining mechanisms in human cells. In contrast with previous studies in mice, canonical nonhomologous end-joining involving DNA ligase IV generates translocations, including a translocation found in cancers.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2014.08.002