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

Hind Ghezraoui, Marion Piganeau, Benjamin Renouf, Jean Baptiste Renaud, Annahita Sallmyr, Brian L Ruis, Sehyun Oh, Alan E. Tomkinson, Eric A Hendrickson, Carine Giovannangeli, Maria Jasin, Erika Brunet

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186 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)829-842
Number of pages14
JournalMolecular Cell
Volume55
Issue number6
DOIs
StatePublished - Sep 18 2014

Bibliographical note

Funding Information:
We thank Michael Lieber (USC) and Penny Jeggo (Sussex) for cell lines; Jean-Paul Concordet, Marine Charpentier, and Anne de Cian (MNHN) for discussions and technical assistance; Sangamo BioSciences, especially Fyodor Urnov and Lei Zhang, for providing ZFNs; and members of the Jasin laboratory, especially Francesca Cavallo and Gemma Regan-Mochrie. This work was supported by La Ligue Nationale contre le Cancer (H.G), Le Canceropole IDF (M.P.), an ANR grant ANR-12-JSV6-0005 (B.R.), and NIH grants to A.E.T. (GM047251, ES012512, and NCI P30CA118100), E.A.H. (GM088351 and CA15446), and M.J. (GM054668).

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