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

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

Author information

1
Museum National d'Histoire Naturelle, 43 rue Cuvier, F-75005 Paris, France; CNRS, UMR7196, 43 rue Cuvier, F-75005 Paris, France; Inserm, U1154, 43 rue Cuvier, F-75005 Paris, France.
2
Department of Internal Medicine and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA.
3
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
4
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: m-jasin@ski.mskcc.org.
5
Museum National d'Histoire Naturelle, 43 rue Cuvier, F-75005 Paris, France; CNRS, UMR7196, 43 rue Cuvier, F-75005 Paris, France; Inserm, U1154, 43 rue Cuvier, F-75005 Paris, France. Electronic address: ebrunet@mnhn.fr.

Abstract

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.

PMID:
25201414
PMCID:
PMC4398060
DOI:
10.1016/j.molcel.2014.08.002
[Indexed for MEDLINE]
Free PMC Article

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