The mechanism of human nonhomologous DNA end joining
Open accessAbstract
Double-strand breaks are common in all living cells, and there are two major pathways for their repair. In eukaryotes, homologous recombination is restricted to late S or G(2), whereas nonhomologous DNA end joining (NHEJ) can occur throughout the cell cycle and is the major pathway for the repair of double-strand breaks in multicellular eukaryotes. NHEJ is distinctive for the flexibility of the nuclease, polymerase, and ligase activities that are used. This flexibility permits NHEJ to function on the wide range of possible substrate configurations that can arise when double-strand breaks occur, particularly at sites of oxidative damage or ionizing radiation. NHEJ does not return the local DNA to its original sequence, thus accounting for the wide range of end results. Part of this heterogeneity arises from the diversity of the DNA ends, but much of it arises from the many alternative ways in which the nuclease, polymerases, and ligase can act during NHEJ. Physiologic double-strand break processes make use of the imprecision of NHEJ in generating antigen receptor diversity. Pathologically, the imprecision of NHEJ contributes to genome mutations that arise over time.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NHEJ arises from faulty repair of DNA double-strand breaks and is more error-prone than NAHR.
“NHEJ occurs as a result of the aberrant repair of DNA double strand breaks and is guided entirely by the information contained within or near the DNA lesion for repair, which makes it error prone as compared to NAHR (Lieber, 2008) (Figure 2B).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Lieber, 2008
In most circumstances, NHEJ is the predominant repair mechanism for DSBs generated by ZFNs, and this repair pathway is attended with nucleotide insertions, deletions or frame-shift mutation leading to gene disruption.
“However, the HR pathway needs an externally provided homologous DNA template; and thus in most circumstances, NHEJ is the predominant repair mechanism for DSBs generated by ZFNs. This repair pathway is attended with nucleotide insertions, deletions or frame-shift mutation [22], leading to gene disruption.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [22]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair
Walker, J. R., Corpina, R. A., & Goldberg, J. D. (2001) · Nature · doi:10.1038/35088000 · Cited by 1,216 · see citing works
Ma, Y., Pannicke, U., Schwarz, K., & Lieber, M. R. (2002) · Cell · doi:10.1016/s0092-8674(02)00671-2 · Cited by 1,166 · see citing works
Self-citationRiballo, E., Kühne, M., Rief, N., Doherty, A., Smith, G. C. M., Recio, M.-J., Reis, C., Dahm, K., Fricke, A., Krempler, A., et al. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.10.029 · Cited by 837 · see citing works
XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining
Ahnesorg, P., Smith, P., & Jackson, S. P. (2006) · Cell · doi:10.1016/j.cell.2005.12.031 · Cited by 794 · see citing works
Moore, J. K., & Haber, J. E. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2164 · Cited by 728 · see citing works
Buck, D., Malivert, L., de Chasseval, R., Barraud, A., Fondanèche, M.-C., Sanal, O., Plebani, A., Stéphan, J.-L., Hufnagel, M., le Deist, F., et al. (2006) · Cell · doi:10.1016/j.cell.2005.12.030 · Cited by 722 · see citing works
Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells
Grawunder, U., Wilm, M. S., Wu, X., Kulesza, P., Wilson, T. E., Mann, M., & Lieber, M. R. (1997) · Nature · doi:10.1038/41358 · Cited by 694 · see citing works
Self-citationIgH class switching and translocations use a robust non-classical end-joining pathway
Yan, C. T., Boboilă, C., Souza, E. K., Franco, S., Hickernell, T. R., Murphy, M., Gumaste, S., Geyer, M. B., Zarrin, A. A., Manis, J. P., et al. (2007) · Nature · doi:10.1038/nature06020 · Cited by 598 · see citing works
Sonoda, E., Hochegger, H., Saberi, A., Taniguchi, Y., & Takeda, S. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.05.022 · Cited by 527 · see citing works
Lack of N Regions in Antigen Receptor Variable Region Genes of TdT-Deficient Lymphocytes
Komori, T., Okada, A., Stewart, V., & Alt, F. W. (1993) · Science · doi:10.1126/science.8356451 · Cited by 483 · see citing works
Mice Lacking TdT: Mature Animals with an Immature Lymphocyte Repertoire
Gilfillan, S., Dierich, A., LeMeur, M., Benoist, C. O., & Mathis, D. J. (1993) · Science · doi:10.1126/science.8356452 · Cited by 447 · see citing works
Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks
Uematsu, N., Weterings, E., Yano, K., Morotomi‐Yano, K., Jakob, B., Taucher-Scholz, G., Mari, P., van Gent, D. C., Chen, B. P. C., & Chen, D. J. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200608077 · Cited by 414 · see citing works
Nonhomologous End Joining in Yeast
Daley, J. M., Palmbos, P. L., Wu, D. L., & Wilson, T. E. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.113340 · Cited by 408 · see citing works
A means to a DNA end: the many roles of Ku
Downs, J. A., & Jackson, S. P. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1367 · Cited by 393 · see citing works
Ma, N. J.-L., Kim, E. M., Haber, J. E., & Lee, S. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.23.8820-8828.2003 · Cited by 366 · see citing works
A Biochemically Defined System for Mammalian Nonhomologous DNA End Joining
Ma, Y., Lu, H., Tippin, B. L., Goodman, M. F., Shimazaki, N., Koiwai, O., Hsieh, C., Schwarz, K., & Lieber, M. R. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.11.017 · Cited by 357 · see citing works
Self-citationDNA‐PK autophosphorylation facilitates Artemis endonuclease activity
Goodarzi, A. A., Yu, Y., Riballo, E., Douglas, P., Walker, S. A., Ye, R., Härer, C. J., Marchetti, C., MORRICE, N. A., Jeggo, P. A., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601255 · Cited by 342 · see citing works
DNA Ligase III as a Candidate Component of Backup Pathways of Nonhomologous End Joining
Wang, H., Rosidi, B., Perrault, A. R., Wang, M., Zhang, L., Windhofer, F., & Iliakis, G. E. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3055 · Cited by 334 · see citing works
DNA double strand break repair and chromosomal translocation: Lessons from animal models
Ferguson, D. O., & Alt, F. W. (2001) · Oncogene · doi:10.1038/sj.onc.1204767 · Cited by 333 · see citing works
Rag mutations reveal robust alternative end joining
Corneo, B., Wendland, R. L., Deriano, L., Cui, X., Klein, I. A., Wong, S.-Y., Arnal, S. M., Holub, A. J., Weller, G. R., Pancake, B. A., et al. (2007) · Nature · doi:10.1038/nature06168 · Cited by 331 · see citing works
Yaneva, M., Kowalewski, T., & Lieber, M. R. (1997) · The EMBO Journal · doi:10.1093/emboj/16.16.5098 · Cited by 324 · see citing works
Self-citationMahajan, K. N., Nick McElhinny, S. A., Mitchell, B. S., & Ramsden, D. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5194-5202.2002 · Cited by 293 · see citing works
Chappell, C., Hanakahi, L. A., Karimi‐Busheri, F., Weinfeld, M., & West, S. C. (2002) · The EMBO Journal · doi:10.1093/emboj/21.11.2827 · Cited by 275 · see citing works
Chu, G. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.39.24097 · Cited by 270 · see citing works
Falzon, M., Fewell, J. W., & Kuff, E. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82233-5 · Cited by 245 · see citing works
Yoo, S. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.24.4679 · Cited by 228 · see citing works
Gong, C., Bongiorno, P., Martins, A., Stephanou, N. C., Zhu, H., Shuman, S., & Glickman, M. S. (2005) · Nature Structural & Molecular Biology · doi:10.1038/nsmb915 · Cited by 215 · see citing works
The DNA‐dependent protein kinase: the director at the end
Meek, K., Gupta, S., Ramsden, D. A., & Lees‐Miller, S. P. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00162.x · Cited by 213 · see citing works
Efficient Processing of DNA Ends during Yeast Nonhomologous End Joining
Wilson, T. E., & Lieber, M. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.33.23599 · Cited by 211 · see citing works
Self-citationCernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends
Tsai, C. J., Kim, S. A., & Chu, G. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702620104 · Cited by 194 · see citing works
Meek, K., Douglas, P., Cui, X., Ding, Q., & Lees‐Miller, S. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02366-06 · Cited by 193 · see citing works
The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps
Ma, Y., Schwarz, K., & Lieber, M. R. (2005) · DNA repair · doi:10.1016/j.dnarep.2005.04.013 · Cited by 191 · see citing works
Self-citationBertocci, B., Smet, A. D., Weill, J., & Reynaud, C. (2006) · Immunity · doi:10.1016/j.immuni.2006.04.013 · Cited by 186 · see citing works
The X family portrait: Structural insights into biological functions of X family polymerases
Moon, A. F., García–Díaz, M., Batra, V. K., Beard, W. A., Bębenek, K., Kunkel, T. A., Wilson, S. H., & Pedersen, L. C. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.05.009 · Cited by 185 · see citing works
Lieber, M. R., Yu, K., & Raghavan, S. C. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.05.013 · Cited by 185 · see citing works
Self-citationModesti, M., Hesse, J. E., & Gellert, M. (1999) · The EMBO Journal · doi:10.1093/emboj/18.7.2008 · Cited by 183 · see citing works
XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps
Gu, J., Lu, H., Tippin, B. L., Shimazaki, N., Goodman, M. F., & Lieber, M. R. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601559 · Cited by 180 · see citing works
Self-citationProductive and Nonproductive Complexes of Ku and DNA-Dependent Protein Kinase at DNA Termini
West, R. B., Yaneva, M., & Lieber, M. R. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.10.5908 · Cited by 170 · see citing works
Self-citationFormation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70
Weinstock, D. M., Brunet, E., & Jasin, M. (2007) · Nature Cell Biology · doi:10.1038/ncb1624 · Cited by 167 · see citing works
Cathepsin L activity controls adipogenesis and glucose tolerance
Yang, M., Zhang, Y., Pan, J., Sun, J., Liu, J., Libby, P., Sukhova, G. K., Doria, A., Katunuma, N., Peroni, O. D., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1623 · Cited by 167 · see citing works
Nonhomologous End-Joining in Bacteria: A Microbial Perspective
Pitcher, R. S., Brissett, N. C., & Doherty, A. J. (2007) · Annual Review of Microbiology · doi:10.1146/annurev.micro.61.080706.093354 · Cited by 163 · see citing works
Jäger, U., Böcskör, S., Le, T., Mitterbauer, G., Bolz, I., Chott, A., Kneba, M., Mannhalter, C., & Nadel, B. (2000) · Blood · doi:10.1182/blood.v95.11.3520 · Cited by 161 · see citing works
Adachi, N., Ishino, T., Ishii, Y., Takeda, S., & Koyama, H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201271098 · Cited by 155 · see citing works
Deletion of Ku70, Ku80, or Both Causes Early Aging without Substantially Increased Cancer
Li, H., Vogel, H. S., Holcomb, V. B., Gu, Y., & Hasty, P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00785-07 · Cited by 151 · see citing works
Gu, J., Lu, H., Tsai, A. G., Schwarz, K., & Lieber, M. R. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm579 · Cited by 136 · see citing works
Self-citationBiochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks
Povirk, L. F. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.05.016 · Cited by 131 · see citing works
Ageing, repetitive genomes and DNA damage
Lieber, M. R., & Karanjawala, Z. E. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1281 · Cited by 126 · see citing works
Self-citationNiewolik, D., Pannicke, U., Lu, H., Ma, Y., Wang, L.-C. V., Kulesza, P., Zandi, E., Lieber, M. R., & Schwarz, K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606023200 · Cited by 118 · see citing works
Self-citationDNA Joint Dependence of Pol X Family Polymerase Action in Nonhomologous End Joining
Daley, J. M., Laan, R. L. V., Suresh, A., & Wilson, T. E. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505277200 · Cited by 117 · see citing works
Tseng, H.-M., & Tomkinson, A. E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206861200 · Cited by 111 · see citing works
Activation of DNA-dependent Protein Kinase by Single-stranded DNA Ends
Hammarsten, O., DeFazio, L. G., & Chu, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.3.1541 · Cited by 109 · see citing works
Stephanou, N. C., Gao, F., Bongiorno, P., et al. (2007) · Journal of Bacteriology · doi:10.1128/jb.00332-07 · Cited by 100 · see citing works
van Heemst, D., Brugmans, L., Verkaik, N. S., & van Gent, D. C. (2003) · DNA repair · doi:10.1016/j.dnarep.2003.09.004 · Cited by 83 · see citing works
Marked Dependence on Growth State of Backup Pathways of NHEJ
Windhofer, F., Wu, W., Wang, M., Singh, S. K., Saha, J., Rosidi, B., & Iliakis, G. E. (2007) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2007.04.038 · Cited by 53 · see citing works
Jovanović, M. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj504 · Cited by 39 · see citing works
Bradshaw, J. L. (1993) · Science · doi:10.1126/science.261.5129.1755 · Cited by 6 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Adachi, N., Ishino, T., Ishii, Y., Takeda, S., and Koyama, H. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 12109 -12113
- Tsai, C. J., Kim, S. A., and Chu, G. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 7851-7856
Cited by
Sorted by citations
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092 · see citing works
The 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 · see citing works
Self-citationMechanisms of change in gene copy number
Hastings, P. J., Lupski, J. R., Rosenberg, S. M., & Ira, G. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2593 · Cited by 1,316 · see citing works
Copy number variation in human health, disease, and evolution
Zhang, F., Gu, W., Hurles, M. E., & Lupski, J. R. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.9.081307.164217 · Cited by 1,207 · see citing works
CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics
Malhotra, D., & Sebat, J. (2012) · Cell · doi:10.1016/j.cell.2012.02.039 · Cited by 854 · see citing works
Thompson, L. H. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.06.002 · Cited by 357 · see citing works
Assembly and function of DNA double-strand break repair foci in mammalian cells
Bekker-Jensen, S., & Mailand, N. (2010) · DNA Repair · doi:10.1016/j.dnarep.2010.09.010 · Cited by 338 · see citing works
Collaboration and competition between DNA double‐strand break repair pathways
Kass, E. M., & Jasin, M. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.057 · Cited by 326 · see citing works
Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
Jiang, Y., Qian, X., Shen, J., Wang, Y., Li, X., Liu, R., Xia, Y., Chen, Q., Peng, G., Lin, S.-Y., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3209 · Cited by 208 · see citing works
Mao, Z., Tian, X., Van Meter, M., Ke, Z., Gorbunova, V., & Seluanov, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200583109 · Cited by 176 · see citing works
Poulsen, M., Lukas, C., Lukas, J., Bekker-Jensen, S., & Mailand, N. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201109100 · Cited by 146 · see citing works
DNA repair and aging: The impact of the p53 family
Nicolai, S., Rossi, A., Di Daniele, N., Melino, G., Annicchiarico-Petruzzelli, M., & Raschellà, G. (2015) · Aging · doi:10.18632/aging.100858 · Cited by 118 · see citing works
XLF regulates filament architecture of the XRCC4.ligase IV complex
Hammel, M., Yu, Y., Fang, S., Lees-Miller, S. P., & Tainer, J. A. (2010) · Structure · doi:10.1016/j.str.2010.09.009 · Cited by 116 · see citing works
Schwartz, R. A., Carson, C. T., Schuberth, C., & Weitzman, M. D. (2009) · Journal of Virology · doi:10.1128/jvi.00318-09 · Cited by 115 · see citing works
Peng, Y., Liao, Q., Tan, W., Peng, C., Hu, Z., Chen, Y., Li, Z., Li, J., Zhen, B., Zhu, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09232-8 · Cited by 104 · see citing works
Newer Gene Editing Technologies toward HIV Gene Therapy
Manjunath, N., Yi, G., Dang, Y., & Shankar, P. (2013) · Viruses · doi:10.3390/v5112748 · Cited by 77 · see citing works
Escape from Telomere-Driven Crisis Is DNA Ligase III Dependent
Jones, R. E., Oh, S., Grimstead, J. W., Zimbric, J., Roger, L., Heppel, N. H., Ashelford, K. E., Liddiard, K., Hendrickson, E. A., & Baird, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.007 · Cited by 74 · see citing works
Zhang, Y., Chang, J.-F., Sun, J., Chen, L., Yang, X.-M., Tang, H.-Y., Jing, Y.-Y., Kang, X., He, Z.-M., Wu, J.-Y., et al. (2018) · Journal of Cell Science · doi:10.1242/jcs.215525 · Cited by 45 · see citing works
Coordination of DNA-PK activation and nuclease processing of DNA termini in NHEJ
Pawelczak, K. S., Bennett, S. M., & Turchi, J. J. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3368 · Cited by 33 · see citing works
- Authors
- Lieber, M. R.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Lieber, Michael R.
- ORCID
- Lieber, Michael R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 283
- Issue
- 1
- Pages
- 1-5
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1965531809
- Cited by
- 720
- References
- 56
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 27 · 2023: 26 · 2022: 31 · 2021: 36 · 2020: 37 · 2019: 29 · 2018: 27 · 2017: 34 · 2016: 35 · 2015: 53 · 2014: 46 · 2013: 45 · 2012: 49
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- non-homologous end joining, DNA double-strand break repair, DNA ligase IV, DNA polymerase IV, DNA nuclease activity, oxidative DNA damage, ionizing radiation, antigen receptor diversity, genomic instability, homologous recombination
- MeSH terms
- DNA-Directed DNA Polymerase, DNA Repair, DNA Helicases, Humans, Models, Biological, DNA Ligases, DNA Repair Enzymes, DNA Breaks, Double-Stranded
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
