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Chromosomal Translocations in Human Cells Are Generated by Canonical Nonhomologous End-Joining
Open accessAbstract
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.
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“form of Cas9 that generates single-stranded break rather than DSB) to generate paired nicks on the two strands of target sequence can significantly increase target specificity because off-target single nicks are faithfully repaired.51”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [51]
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BackgroundInfluentialMultiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339 · cited 1×
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Sule, A. D., Golding, S. E., Ahmad, S. F., Watson, J., Ahmed, M. H., Kellogg, G. E., Bernaś, T., Koebley, S. R., Reed, J. C., Povirk, L. F., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04550-5 · Cited by 9
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Microhomology‐mediated repair machinery and its relationship with HPV‐mediated oncogenesis
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“49,50 Flap endonuclease 1 (FEN1) additionally has been found to play a significant role in MMEJ.”
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Maddalo, D., & Ventura, A. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0726 · Cited by 8
“The event that initiates chromosomal rearrangements is the concomitant occurrence of double-strand DNA breaks in two distinct regions of the genome followed by canonical non-homologous end joining (NHEJ) of the two breakpoints (8, 9).”
Generation of chromosome 1p/19q co-deletion by CRISPR/Cas9-guided genomic editing
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“However, the analyzed genomic fusion alleles of the experimentally induced t(4; 11) or t(6; 19) chromosomal translocations displayed the same typical characteristics that have been diagnosed in the genomic DNA of patients with MLL-r acute leukemia.”
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“Nonetheless, a subset of chromosomal translocations may be generated through the canonical NHEJ pathway ( 68 , 69 ).”
Bader, A. S., & Bushell, M. (2023) · Nature Communications · doi:10.1038/s41467-023-44167-1 · Cited by 11
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Use of theHPRTgene to study nuclease-induced DNA double-strand break repair
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“Consistent with this, chromosomal translocations induced by wild-type Cas9 involve deletions less frequently than natural translocations or translocations induced by paired Cas9 nickases (55).”
BackgroundUnder the Influence: Cas9 Ends and DNA Repair Outcomes
Jasin, M. (2018) · The CRISPR Journal · doi:10.1089/crispr.2018.29014.jas · Cited by 8
“For example, translocation junctions generated after Cas9 cleavage of two chromosomes show frequent 1-bp insertions that could have arisen from polymerase fill-in of a 1-base overhang.(6,7) Retention of 5¢ and 3¢ overhangs generated by other nucleases (ZFNs, TALENs, I-SceI) is also observed, again suggesting overhang…”
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Self-citationMechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated
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“Chromosome translocations are primarily caused by the NHEJ pathway, moreover, NHEJ pathway dysregulations are found in almost all types of leukemias [31, 32].”
BackgroundYi, H., Yun, Y., Choi, W. H., Hwang, H.-Y., Cha, J. H., Seok, H., Song, J., Lee, J. H., Oh, S. H., Lee, S.-Y., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102199 · Cited by 5
Alternative Non-homologous End-Joining: Mechanisms and Targeting Strategies in Cancer
Nagaria, P. K., & Rassool, F. V. (2018) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-75836-7_15 · Cited by 4
Hu, C., Doerksen, T., Bugbee, T., Wallace, N. A., & Palinski, R. M. (2022) · Journal of Visualized Experiments · doi:10.3791/62583 · Cited by 6
Genome Editing with Targetable Nucleases
Pelletier, S. W. (2016) · Springer eBooks · doi:10.1007/978-3-319-34148-4_1 · Cited by 4
Pathway choice for DNA double strand break repair
Xu, D., & HuaYu, Z. H. A. O. (2020) · Scientia Sinica Vitae · doi:10.1360/ssv-2020-0196 · Cited by 4
A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinomaPreprint
Achom, M., Sadagopan, A., Bao, C., McBride, F., Xu, Q., Konda, P., Tourdot, R. W., Li, J., Nakhoul, M., Gallant, D. S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.04.552029 · Cited by 4
“Moreover, these fusions can be faithfully modeled in human cells using CRISPR/Cas9 engineering, consistent with a prior study that engineered translocations in human cells using designer nucleases ( 44 ).”
Chromosome breakage-replication/fusion enables rapid DNA amplificationPreprint
Zhang, C., & Pellman, D. S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.17.608415 · Cited by 4
Diblasi, C., & Saitou, M. (2025) · Heredity · doi:10.1038/s41437-025-00785-7 · Cited by 5
Azam, N., Liu, X., Li, X., Ma, L., & Liu, Q. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5809 · Cited by 3
“To investigate the direct role of alt‑EJ in chromosomal translocation formation, studies induced targeted DSBs on distinct chromosomes using site‑specific nucleases such as CRISPR‑Cas9 or I‑SceI endonuclease (104,105).”
ERCC6L2 ensures repair fidelity for staggered-end DNA double-strand breaks
Aird, E. J., Serrano-Benítez, A., Siegner, S. M., Cannavò, E., Belotserkovskaya, R., Gueorguieva, N., Fielden, J., Cullot, G., Ammann, S., Bader, A. S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69843-w · Cited by 4
DNA double-strand repair by nonhomologous end joining and its clinical relevance
Setton, J. S., Bindra, R. S., & Powell, S. N. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803582-5.00009-7 · Cited by 4
Acquired Chromosomal Abnormalities and Their Potential Formation Mechanisms in Solid Tumours
Aygün, N. (2017) · InTech eBooks · doi:10.5772/67733 · Cited by 4
“However, it was reported that c-NHEJ is the predominant mechanism for repair of the double-strand breaks, resulting in translocation formation in human cells [95].”
BackgroundRepair of double-strand breaks by nonhomologous end joining; Its components and their function
Moskwa, P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85679-9.00019-2 · Cited by 3
Febrianti, R. A., Narulita, E., Sulistyaningsih, E., & Addy, H. S. (2025) · Foodborne Pathogens and Disease · doi:10.1089/fpd.2024.0194 · Cited by 3
Breaking the paradigm: early insights from mammalian DNA breakomes
Saayman, X., & Esashi, F. (2021) · FEBS Journal · doi:10.1111/febs.15849 · Cited by 3
Bader, A. S., & Bushell, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.08.471781 · Cited by 3
“…reduced mutations does support the notion of NHEJ being a mutagenic repair process, and the especially the reduction in translocations seen with KU70 and Artemis depletion as genomic rearrangements are thought to commonly be the result NHEJ (Ghezraoui et al, 2014; Cannan and Pederson, 2016).”
BackgroundHow CRISPR Is Revolutionizing the Generation of New Models for Cancer ResearchPreprint
Rivera, F. J. S., & Dow, L. E. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041384 · Cited by 4
Nonhomologous end joining—the importance of end tethering and beyondPreprint
Zha, S., & Yi, G. (2026) · Genes & Development · doi:10.1101/gad.353407.125 · Cited by 5
“Beyond physiological repair, NHEJ also repairs DSBs from ionizing radiation and genotoxic chemotherapy and contributes to oncogenic chromosomal translocations (Ghezraoui et al. 2014).”
White, N., Hu, Y., Chalk, J. A., Kurgan, G., Naseem, A., Schmaljohn, E., Sturgeon, M. L., Cavazza, A., Thrasher, A. J., & Turchiano, G. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag318 · Cited by 2
“These observations suggest previously unrecognized overlap between ostensibly independent repair pathways [ 45 ] and reveal a novel aberration that introduces additional genotoxic risk, both of which merit further investigation.”
López-Muñoz, A. D., Rastrojo, A., Martín, R., & Alcamı́, A. (2022) · Journal of General Virology · doi:10.1099/jgv.0.001797 · Cited by 2
“200 bp (26, 27), we designed both gRNAs targeting the eGFP cassette in HSV-1/2 Red DgG341”
Li, C., Tuerxun, Z., Yang, Y., Li, X., Hui, F., Li, J., Liu, Z., Chen, G., Cai, D., Zhang, H., et al. (2024) · Journal of Integrative Agriculture · doi:10.1016/j.jia.2024.09.011 · Cited by 2
CRISPR-Cas9 in cancer therapeutics
Randhawa, S. (2021) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2021.01.016 · Cited by 2
TALEN-Induced Translocations in Human Cells
Piganeau, M., Renouf, B., Ghezraoui, H., & Brunet, E. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2932-0_9 · Cited by 2
Self-citationCheng, Z., Wang, Y., Guo, L., Li, J., Zhang, W., Zhang, C., Liu, Y., Huang, Y., & Xu, K. (2022) · Radiation Oncology · doi:10.1186/s13014-022-02113-3 · Cited by 3
“In our study, the frequency of chromosome translocations increased with the doses of X-rays, and it showed a positive correlation with the expression of Ku70, which is consistent with what Ghezraoui reported [34].”
BackgroundResultInfluentialRepair of Double-Strand Breaks by Nonhomologous End Joining
Moskwa, P. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803309-8.00019-7 · Cited by 2
Anaplastic Lymphoma Kinase activating mechanisms and signaling pathways
Inghirami, G. (2015) · Frontiers in Bioscience-Scholar · doi:10.2741/s441 · Cited by 2
Dahl-Jessen, M., Terkelsen, T., Bak, R. O., & Jensen, U. B. (2025) · Genome Research · doi:10.1101/gr.278575.123 · Cited by 2
Yan, Y., Shi, G., Li, K., Lei, Y., Wang, Y., Wang, Y., Liu, S., Fernandez, A., Zhou, T., Wang, E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.06.680735 · Cited by 2
Guirouilh‐Barbat, J., Boueya, I. L., Gelot, C., Pennarun, G., Granotier-Beckers, C., Dardillac, E., Yu, W., Lescale, C., Rass, E., Ariste, O., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf468 · Cited by 1
“This translocation is reconstituted in cells with targeted endonuclease-mediated cleavage (here, mediated by TALENs) at specific loci [ 10 ].”
Self-citationLomov, N. A., Nikolaev, N. A., Viushkov, V. S., & Rubtsov, M. A. (2025) · Biochemistry (Moscow) · doi:10.1134/s0006297925602102 · Cited by 1
Collateral DNA Damage Produced by Genome-Editing Drones: Exception or Rule?
Canela, A., Stanlie, A., & Nussenzweig, A. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.012 · Cited by 1
“On a more basic level, nucleotide level detection of breakpoint junctions can allow for in depth analysis of mechanisms of end-joining repair in human cells (Ghezraoui et al., 2014).”
BackgroundJasin, M. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-3509-3_1 · Cited by 3
“Because cancer translocation breakpoint junctions do not typically show homology between the two chromosomal sequences that are joined, NHEJ-based translocation systems are relevant to understanding the joining mechanisms by which oncogenic translocations arise [ 37 ].”
BackgroundSelf-citationMechanisms of Recurrent Chromosomal Translocations
Frock, R. L., Hu, J., & Alt, F. W. (2015) · Springer eBooks · doi:10.1007/978-3-319-19983-2_3 · Cited by 1
“, [ 157 ]); although the relative contribution of A-EJ remains to be determined.”
BackgroundRemoval of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
Abramenkovs, A., & Stenerlöw, B. (2018) · PLoS ONE · doi:10.1371/journal.pone.0209594 · Cited by 1
Base Editing: Efficient Installation of Point Mutations with Minimal Byproducts
Newby, G. A. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0080 · Cited by 1
“…efficiency is generally much higher, especially in nondi-viding cells, and (3) undesired byproducts are much rarer because base editing does not normally create double-strand DNA breaks that trigger indels [11], translocations [12], large deletions [11], rearrangements [13], or p53 activation [14].”
Moskwa, P. (2016) · Cited by 1
The Legacy of George M. Martin: From Segmental Progeroid Syndromes to Antigeroid Syndromes
Poot, M. (2023) · Cytogenetic and Genome Research · doi:10.1159/000537967 · Cited by 2
“Since the thus resected DNA ends do no longer contain their original DNA motifs, they can conceivably be (mis)joined such that translocations may result [22].”
BackgroundNGS Detects Extensive Genomic Alterations in Survivors of Irradiated Normal Human Fibroblast Cells
Soni, A., Beißer, D., Mladenov, E., Höller, M., Wohlers, I., Nikolov, V., Magin, S., Mussfeldt, T., Klein‐Hitpaß, L., Cornforth, M. N., et al. (2024) · Radiation Research · doi:10.1667/rade-24-00094.1 · Cited by 1
“The types of genomic alterations characterized require joining, by c-NHEJ or alt-EJ, of DNA-ends belonging to different DSBs whose original ends drifted apart and found other ends in close proximity during processing ( 11 , 26 ).”
Donaldson, B. (2020) · The Atrium (University of Guelph) · Cited by 1
Microhomology-mediated repair machinery and its relationship with HPV-mediated oncogenesisPreprint
Starrett, G. J., & Chatterjee, S. (2024) · doi:10.22541/au.171006332.24357508/v1 · Cited by 1
Wilson, T. E., Ahmed, S., Winningham, A., & Glover, T. W. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.28.596214 · Cited by 1
Metadata
- 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.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of New Mexico (US)
- University of Minnesota (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Jasin, Maria
- Brunet, Erika
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 55
- Issue
- 6
- Pages
- 829-842
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4398060
- OpenAlex
- W2080290623
- Cited by
- 351
- References
- 68
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 27 · 2023: 24 · 2022: 29 · 2021: 26 · 2020: 33 · 2019: 31 · 2018: 33 · 2017: 38 · 2016: 43 · 2015: 40 · 2014: 2
- FWCI
- 16.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-12, ANR-12-JSV6-0005)
- Ligue Contre le Cancer
- Muséum National d'Histoire Naturelle
- National Institutes of Health (GM047251)
- National Cancer Institute (CA15446, P30CA118100, P01CA092584)
- National Institute of General Medical Sciences (R01GM047251, GM047251, R01GM088351, GM088351, R01GM054668, GM054668)
- National Institute of Environmental Health Sciences (ES012512, R01ES012512)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- chromosomal translocation, non-homologous end joining, alternative NHEJ, DNA ligase IV, XRCC4, breakpoint junctions, microhomology, DNA double-strand breaks, designer nucleases, CRISPR/Cas9, species differences, human cells
- MeSH terms
- DNA Ligase ATP, Animals, Chromosomes, Human, Deoxyribonucleases, DNA-Binding Proteins, Humans, DNA Ligases, Species Specificity, Translocation, Genetic, Tumor Cells, Cultured, Sequence Deletion, Mice, DNA End-Joining Repair
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