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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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Cites
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BackgroundNoncanonical views of homology-directed DNA repairPreprint
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C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains
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Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining
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BackgroundDNA Polymerase θ: A Unique Multifunctional End-Joining Machine
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“, ≥2 bp in human cells) of sequence microhomology which may promote base pairing of complementary portions of 3’ ssDNA overhangs (Figure 2, right; Table 1) [51].”
BackgroundResultInfluentialIn vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model
Carreras, A., Pane, L. S., Nitsch, R., Madeyski-Bengtson, K., Porritt, M. J., Akçakaya, P., Taheri‐Ghahfarokhi, A., Ericson, E., Bjursell, M., Pérez-Alcázar, M., et al. (2019) · BMC Biology · doi:10.1186/s12915-018-0624-2 · Cited by 93
“Chromosomal translocations, which result from double-strand breaks in chromosomes and subsequent joining of loose ends of different chromosome arms, may limit the therapeutic use of genomic editing technologies because of their oncogenic potential [43, 44].”
BackgroundA Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma
Msaouel, P., Tannir, N. M., & Walker, C. L. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3296 · Cited by 90
“However, while cNHEJ suppresses translocations in mice, it has recently been found to produce oncogenic chromosomal translocations in humans (21, 28).”
BackgroundIn vivo blunt-end cloning through CRISPR/Cas9-facilitated non-homologous end-joining
Geisinger, J. M., Turan, S., Hernandez, S., Spector, L. P., & Calos, M. P. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1542 · Cited by 86
“(5,6,20,26,36,77) underscore that NHEJ resulting from blunt-end, chemically unmodified DSBs, such as those made by Cas9, are repaired with a high degree of precision.”
InfluentialWhen Genome Maintenance Goes Badly Awry
Kass, E. M., Moynahan, M. E., & Jasin, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.021 · Cited by 84
Self-citationA novel small molecule inhibitor of the DNA repair protein Ku70/80
Weterings, E., Gallegos, A. C., Dominick, L. N., Cooke, L. S., Bartels, T. N., Vágner, J., Matsunaga, T. O., & Mahadevan, D. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.03.014 · Cited by 84
Brunet, E., & Jasin, M. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-0593-1_2 · Cited by 79
“Modeling t(2;5)(p23;q35), found in cases of ALCL, our group showed expression of oncogenic NPM1-ALK kinase activation in human cell lines.”
BackgroundMethodInfluentialSelf-citationVriend, L. E. M., Prakash, R., Chen, C.-C., Vanoli, F., Cavallo, F., Zhang, Y., Jasin, M., & Krawczyk, P. M. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw179 · Cited by 77
“In agreement, single Cas9-generated nicks fail to induce oncogenic chromosomal translocations, which require DSB formation (68).”
BackgroundSelf-citationGenetic and Epigenetic Alterations in Bladder Cancer
Li, H., Duymich, C. E., Weisenberger, D. J., & Liang, G. (2016) · International Neurourology Journal · doi:10.5213/inj.1632752.376 · Cited by 80
“Chromosomal Rearrangements Chromosomal rearrangements, namely the concomitant result of aberrant nonhomologous end joining [33], may result in oncogene formation and therefore may initiate tumorigenesis [30,34] or increasing oncogene expression [35].”
BackgroundKitano, Y., Nishimura, S., Kato, T., Ueda, A., Takigawa, K., Umekage, M., Nomura, M., Kawakami, A., Ogawa, H., Xu, H., et al. (2022) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2022.05.010 · Cited by 80
“There is also a risk of chromosomal translocation when double-strand breaks are introduced into different chromosomes.(20,21) Multiplexed gene disruption is necessary for the generation of hypoimmunogenic iPSCs.”
Nilsson, D., Pettersson, M., Gustavsson, P., Förster, A., Hofmeister, W., Wincent, J., Zachariadis, V., Anderlid, B., Nordgren, A., Mäkitie, O., et al. (2016) · Human Mutation · doi:10.1002/humu.23146 · Cited by 74
“…notion that mechanisms other than NHEJ and NAHR underlie the formation of some balanced translocations is provided by studies on human cells, 6% of translocation junctions generated in vitro show the presence of templated insertions varying from 20 bp to several hundred bp [Ghezraoui et al., 2014].”
BackgroundInfluentialRegulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution
Hanscom, T., & McVey, M. (2020) · Cells · doi:10.3390/cells9071657 · Cited by 79
“For example, in human cells, cNHEJ is responsible for a majority of chromosomal translocations resulting from ionizing radiation and nuclease-induced breaks [14].”
BackgroundRepair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ
Yu, W., Lescale, C., Babin, L., Bedora-Faure, M., Hasse, H. L., Baron, L., Demangel, C., Yélamos, J., Brunet, E., & Deriano, L. (2020) · Nature Communications · doi:10.1038/s41467-020-19060-w · Cited by 68
Self-citationStrategies for Efficient Genome Editing Using CRISPR-Cas9
Farboud, B., Severson, A. F., & Meyer, B. J. (2018) · Genetics · doi:10.1534/genetics.118.301775 · Cited by 66
Targeted genomic translocations and inversions generated using a paired prime editing strategy
Kweon, J., Hwang, H., Ryu, H., Jang, A.-H., Kim, D., & Kim, Y. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.09.008 · Cited by 67
CRISPR-induced double-strand breaks trigger recombination between homologous chromosome arms
Brunner, E., Yagi, R., Debrunner, M., Beck-Schneider, D., Burger, A., Escher, E., Mosimann, C., Hausmann, G., & Basler, K. (2019) · Life Science Alliance · doi:10.26508/lsa.201800267 · Cited by 65
“Because Cas9 activity may often cause the break of both homologs, such recombination events may not only be based on homologous recombination but may also result by breakage/fusion events involving NHEJ that lead to a crosswise ligation of the chromosome arms (15, 16, 17, 18, 19, 20, 21, 22).”
BackgroundThe genomic landscape of 8-oxodG reveals enrichment at specific inherently fragile promoters
Gorini, F., Scala, G., Di Palo, G., Dellino, G. I., Cocozza, S., Pelicci, P. G., Lania, L., Majello, B., & Amente, S. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa175 · Cited by 67
“Since NHEJ is considered an error-prone repair pathway (66), and MCF10A promoter introns (i.”
BackgroundRisky business: Microhomology-mediated end joining
Sinha, S., Villarreal, D. D., Shim, E. Y., & Lee, S. E. (2016) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2015.12.005 · Cited by 66
Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome
Lecoq, A.-L., Stratakis, C. A., Viengchareun, S., Chaligné, R., Tosca, L., Deméocq, V., Hage, M. P., Berthon, A. S., Faucz, F. R., Hanna, P., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.92184 · Cited by 65
“In both adenoma samples, breakpoints close to the GIPR gene were characterized at base pair resolution by conventional Sanger sequencing of the PCR fragments (Figure 3B), showing a junction of canonical nonhomologous end-joining typical of chromosomal translocations in human cells (14).”
BackgroundThe Determinant of DNA Repair Pathway Choices in Ionising Radiation‐Induced DNA Double‐Strand Breaks
Zhao, L., Bao, C., Shang, Y., He, X., Ma, C., Lei, X., Mi, D., & Sun, Y. (2020) · BioMed Research International · doi:10.1155/2020/4834965 · Cited by 69
A versatile reporter system for CRISPR-mediated chromosomal rearrangements
Li, Y., Park, A. I., Mou, H., Colpan, C., Bizhanova, A., Akama‐Garren, E. H., Joshi, N., Hendrickson, E. A., Feldser, D. M., Yin, H., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0680-7 · Cited by 64
“The role of LIG4 in mediating the rearrangements and the application of CRISPR-Cas9 to induce inversions and deletions in cells and in mice have been reported by recent studies [16, 19, 21, 31].”
BackgroundMethodInfluentialSelf-citationGenomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells
So, A., Guen, T. L., López, B. S., & Guirouilh‐Barbat, J. (2017) · FEBS Journal · doi:10.1111/febs.14053 · Cited by 75
Guo, C., Nakazawa, Y., Woodbine, L. J., Björkman, A., Shimada, M., Fawcett, H., Jia, N., Ohyama, K., Li, T., Nagayama, Y., et al. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.06.007 · Cited by 63
On- and off-target effects of paired CRISPR-Cas nickase in primary human cells
Klermund, J., Rhiel, M., Köcher, T., Chmielewski, K. O., Bischof, J., Andrieux, G., el Gaz, M., Hainzl, S., Boerries, M., Cornu, T. I., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.006 · Cited by 65
“26,37,42 Furthermore, in cells edited with paired CRISPR-Cas9 nickases, translocations between the target site and known off-target sites could not be detected by qualitative translocation PCR. 38 However, a systematic genome-wide and sensitive analysis of on-and off-target aberrations in…”
TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
Gómez-Herreros, F., Zagnoli-Vieira, G., Ntai, I., Martínez-Macías, M. I., Anderson, R. M., Herrero-Ruíz, A., & Caldecott, K. W. (2017) · Nature Communications · doi:10.1038/s41467-017-00307-y · Cited by 65
Mechanisms of germ line genome instability
Kim, S., Peterson, S., Jasin, M., & Keeney, S. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.02.019 · Cited by 57
Self-citationVanoli, F., Tomishima, M. J., Feng, W., Lamribet, K., Babin, L., Brunet, E., & Jasin, M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700622114 · Cited by 56
“Spraggon L, et al. (2017) Generation of conditional oncogenic chromosomal translocations using CRISPR-Cas9 genomic editing and homology-directed repair.”
BackgroundInfluentialSelf-citationSchipler, A., Mladenova, V., Soni, A., Nikolov, V., Saha, J., Mladenov, E., & Iliakis, G. E. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw487 · Cited by 56
“Since HRR is unlikely to catalyze their formation, c-NHEJ and alt-EJ become natural candidates, with alt-EJ featuring more prominently, although the actual relative contribution is debated and likely to also be cell-cycle-phase and DSB-site dependent (16,44,51).”
Han, J., Ruan, C., Huen, M. S. Y., Wang, J., Xie, A., Fu, C. M., Liu, T., & Huang, J. (2017) · Nature Communications · doi:10.1038/s41467-017-01759-y · Cited by 55
Detection and Modulation of DNA Translocations During Multi-Gene Genome Editing in T Cells
Bothmer, A., Gareau, K. W., Abdulkerim, H. S., Buquicchio, F. A., Cohen, L. A., Viswanathan, R., Zuris, J. A., Marco, E., Fernández, C. A., Myer, V. E., et al. (2020) · The CRISPR Journal · doi:10.1089/crispr.2019.0074 · Cited by 56
“29 We reasoned that if we engaged ‰ Fig.”
From gene editing to genome engineering: restructuring plant chromosomes via CRISPR/Cas
Schmidt, C., Schindele, P., & Puchta, H. (2019) · aBIOTECH · doi:10.1007/s42994-019-00002-0 · Cited by 53
Genome Protection by DNA Polymerase θ
Wood, R. D., & Doublié, S. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072920-041046 · Cited by 50
CRISPR therapeutic tools for complex genetic disorders and cancer (Review)
Baliou, S., Adamaki, M., Kyriakopoulos, A. M., Spandidos, D. A., Panayiotidis, M. I., Christodoulou, I., & Zoumpourlis, V. C. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4434 · Cited by 55
“In addition, the chromosomal translocation t(8;21)/RUNX1-ETO was introduced into 293 cells and CD34+ human hematopoietic progenitor cells with the use of the CRISPR system, successfully recapitulating the phenotype of acute myeloid leukemia (AML).”
InfluentialDiscovery and development of novel DNA-PK inhibitors by targeting the unique Ku–DNA interaction
Gavande, N. S., VanderVere-Carozza, P. S., Pawelczak, K. S., Mendoza-Munoz, P. L., Vernon, T. L., Hanakahi, L. A., Summerlin, M., Dynlacht, J. R., Farmer, A. H., Sears, C. R., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa934 · Cited by 46
“It is well understood that random insertion of a dsDNA molecule, a technique utilized for generating stably transfected cell lines for decades, is driven by NHEJ (48;52-55).”
BackgroundSpecificity of oligonucleotide gene therapy (OGT) agents
Nedorezova, D. D., Dubovichenko, M. V., Belyaeva, E. P., Grigorieva, E. D., Peresadina, A. V., & Kolpashchikov, D. M. (2022) · Theranostics · doi:10.7150/thno.77830 · Cited by 50
Biechonski, S., Yassin, M., & Milyavsky, M. (2017) · Carcinogenesis · doi:10.1093/carcin/bgx002 · Cited by 54
“This pathway is considered fast but error prone, which may account for most of the genomic structural variants and chromosomal translocations found in human cancer (68,69).”
Background
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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