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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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

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Genetic Translocation
Clustered Regularly Interspaced Short Palindromic Repeats
Neoplasms
Carcinogenesis
Chromosomes
Proteins

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Ghezraoui, H., Piganeau, M., Renouf, B., Renaud, J. B., Sallmyr, A., Ruis, B. L., ... Brunet, E. (2014). Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining. Molecular Cell, 55(6), 829-842. https://doi.org/10.1016/j.molcel.2014.08.002

Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining. / Ghezraoui, Hind; Piganeau, Marion; Renouf, Benjamin; Renaud, Jean Baptiste; Sallmyr, Annahita; Ruis, Brian L; Oh, Sehyun; Tomkinson, Alan E.; Hendrickson, Eric A; Giovannangeli, Carine; Jasin, Maria; Brunet, Erika.

In: Molecular Cell, Vol. 55, No. 6, 18.09.2014, p. 829-842.

Research output: Contribution to journalArticle

Ghezraoui, H, Piganeau, M, Renouf, B, Renaud, JB, Sallmyr, A, Ruis, BL, Oh, S, Tomkinson, AE, Hendrickson, EA, Giovannangeli, C, Jasin, M & Brunet, E 2014, 'Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining', Molecular Cell, vol. 55, no. 6, pp. 829-842. https://doi.org/10.1016/j.molcel.2014.08.002
Ghezraoui, Hind ; Piganeau, Marion ; Renouf, Benjamin ; Renaud, Jean Baptiste ; Sallmyr, Annahita ; Ruis, Brian L ; Oh, Sehyun ; Tomkinson, Alan E. ; Hendrickson, Eric A ; Giovannangeli, Carine ; Jasin, Maria ; Brunet, Erika. / Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining. In: Molecular Cell. 2014 ; Vol. 55, No. 6. pp. 829-842.
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