Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining Journal Article
| Authors: | Ghezraoui, H.; Piganeau, M.; Renouf, B.; Renaud, J. B.; Sallmyr, A.; Ruis, B.; Oh, S.; Tomkinson, A. E.; Hendrickson, E. A.; Giovannangeli, C.; Jasin, M.; Brunet, E. |
| Article Title: | Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining |
| 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. |
| Keywords: | controlled study; unclassified drug; dna binding protein; gene translocation; human cell; gene deletion; genetics; dna-binding proteins; sequence deletion; chromosome 19; mouse; phenotype; animal; animals; mice; tumor cell culture; tumor cells, cultured; wild type; physiology; carcinogenesis; species specificity; species difference; nuclease; chromosome rearrangement; chromosome translocation; double stranded dna break; translocation, genetic; sequence homology; xrcc4 protein; polydeoxyribonucleotide synthase; chromosome deletion; chromosomes, human; human chromosome; cell mutant; pre b lymphocyte; dna ligases; deoxyribonuclease; chromosome 22; deoxyribonucleases; human versus animal comparison; polydeoxyribonucleotide synthase (atp); dna end-joining repair; xrcc4 protein, human; dna end joining repair; humans; human; article; crispr associated protein; dna ligase iv; protein talen; protein zfn |
| Journal Title: | Molecular Cell |
| Volume: | 55 |
| Issue: | 6 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2014-09-18 |
| Start Page: | 829 |
| End Page: | 842 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2014.08.002 |
| PUBMED: | 25201414 |
| PROVIDER: | scopus |
| PMCID: | PMC4398060 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
