Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining

Mol Cell. 2014 Sep 18;55(6):829-842. doi: 10.1016/j.molcel.2014.08.002. Epub 2014 Sep 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomes, Human
  • DNA End-Joining Repair*
  • DNA Ligase ATP
  • DNA Ligases / genetics*
  • DNA-Binding Proteins / genetics*
  • Deoxyribonucleases / physiology*
  • Humans
  • Mice
  • Sequence Deletion
  • Species Specificity
  • Translocation, Genetic / genetics*
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • LIG4 protein, human
  • XRCC4 protein, human
  • Deoxyribonucleases
  • DNA Ligases
  • DNA Ligase ATP