The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
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
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116 · cited 4×
“…et al., 1998), suggesting that DSBs with blunt DNA ends may not give rise to such translocations. nCas9, a Cas9 nickase due to a D10A mutation (Jinek et al., 2012), can generate DSBs with overhangs if two gRNAs are used that cleave opposite strands (i.e., paired nicks) (Mali et al., 2013a;…”
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×
“We also tested Cas9-dependent induction of DSBs (Cong et al., 2013; Mali et al., 2013b) for translocation formation.”
MethodRNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210 · cited 3×
“Paired nicks generated by nCas9 have the potential to substantially increase cleavage specificity, given that two gRNAs are required per DSB (Mali et al., 2013a; Ran et al., 2013), and we have determined that nCas9-generated paired nicks efficiently induce translocations.”
BackgroundMethodZFN, TALEN, and CRISPR/Cas-based methods for genome engineering
Gaj, T., Gersbach, C. A., & Barbas, C. F. (2013) · Trends in Biotechnology · doi:10.1016/j.tibtech.2013.04.004 · Cited by 3,820 · cited 2×
“To address the role of NHEJ pathways in the joining phase of chromosomal translocation formation, we took advantage of nucleases designed to introduce site-specific DSBs at endogenous loci in human cells (Gaj et al., 2013; Urnov et al., 2010) to induce translocations (Brunet et al.”
BackgroundDouble nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity
Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., Scott, D. A., Inoue, A., Matoba, S., Zhang, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.021 · Cited by 3,299 · cited 2×
“Paired nicks generated by nCas9 have the potential to substantially increase cleavage specificity, given that two gRNAs are required per DSB (Mali et al., 2013a; Ran et al., 2013), and we have determined that nCas9-generated paired nicks efficiently induce translocations.”
BackgroundHigh-Frequency off-Target Mutagenesis Induced by CRISPR-Cas Nucleases in Human Cells
Fu, Y., Foden, J. A., Khayter, C., Maeder, M. L., Reyon, D., Joung, J. K., & Sander, J. D. (2013) · Nature Biotechnology · doi:10.1038/nbt.2623 · Cited by 3,292 · cited 1×
“Because mismatches to the gRNA can be tolerated, however, wild-type Cas9 has been associated with off-target mutagenesis (Fu et al., 2013).”
BackgroundThe mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway
Lieber, M. R. (2010) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.052308.093131 · Cited by 2,882 · cited 1×
“NALM6 junctions without insertions showed longer microhomology than is typical of wild-type cells, raising the possibility that some of the junctions that did not engage TdT did not join by c-NHEJ; alternatively, TdT may have created microhomology in some of these junctions (Lieber, 2010).”
BackgroundGenome editing with engineered zinc finger nucleases
Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S., & Gregory, P. D. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2842 · Cited by 2,285 · cited 2×
“To address the role of NHEJ pathways in the joining phase of chromosomal translocation formation, we took advantage of nucleases designed to introduce site-specific DSBs at endogenous loci in human cells (Gaj et al., 2013; Urnov et al., 2010) to induce translocations (Brunet et al.”
BackgroundMali, P., Aach, J., Stranges, P. B., Esvelt, K. M., Moosburner, M., Kosuri, S., Yang, L., & Church, G. M. (2013) · Nature Biotechnology · doi:10.1038/nbt.2675 · Cited by 1,752 · cited 3×
“Paired nicks generated by nCas9 have the potential to substantially increase cleavage specificity, given that two gRNAs are required per DSB (Mali et al., 2013a; Ran et al., 2013), and we have determined that nCas9-generated paired nicks efficiently induce translocations.”
BackgroundMethodThe impact of translocations and gene fusions on cancer causation
Mitelman, F., Johansson, B., & Mertens, F. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2091 · Cited by 1,400 · cited 1×
“Recurrent reciprocal chromosomal translocations are associated with oncogenesis (Mani and Chinnaiyan, 2010; Mitelman et al., 2007).”
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GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases
Tsai, S. Q., Zheng, Z., Nguyen, N. T., Liebers, M., Topkar, V. V., Thapar, V., Wyvekens, N., Khayter, C., Iafrate, A. J., Le, L. P., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3117 · Cited by 2,268
Kosicki, M., Tomberg, K., & Bradley, A. (2018) · Nature Biotechnology · doi:10.1038/nbt.4192 · Cited by 1,883
Non-homologous DNA end joining and alternative pathways to double-strand break repair
Chang, H. H. Y., Pannunzio, N. R., Adachi, N., & Lieber, M. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.48 · Cited by 1,757
Huang, R., & Zhou, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00648-7 · Cited by 1,015
“In addition, alt-EJ is mainly mediated by the CtIP/ MRN complex.(319) Furthermore, Polθ can indicate the microhomologous DNA ends to support the joining of DNA ends.”
BackgroundPatterns of somatic structural variation in human cancer genomes
Li, Y., Roberts, N. D., Wala, J. A., Shapira, O., Schumacher, S. E., Kumar, K., Khurana, E., Waszak, S., Korbel, J. O., Haber, J. E., et al. (2020) · Nature · doi:10.1038/s41586-019-1913-9 · Cited by 867
“Hypothesis-driven in vitro studies are now beginning to reveal some of the mechanistic processes generating these structures 9–13 , and generate further predictions that can be assessed in the genomics data.”
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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