DNA double-strand break repair pathway choice and cancer
Open accessAbstract
Since DNA double-strand breaks (DSBs) contribute to the genomic instability that drives cancer development, DSB repair pathways serve as important mechanisms for tumor suppression. Thus, genetic lesions, such as BRCA1 and BRCA2 mutations, that disrupt DSB repair are often associated with cancer susceptibility. In addition, recent evidence suggests that DSB "mis-repair", in which DSBs are resolved by an inappropriate repair pathway, can also promote genomic instability and presumably tumorigenesis. This notion has gained currency from recent cancer genome sequencing studies which have uncovered numerous chromosomal rearrangements harboring pathological DNA repair signatures. In this perspective, we discuss the factors that regulate DSB repair pathway choice and their consequences for genome stability and cancer.
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Chromosomal rearrangements accumulate in cancer cells, eventually leading to cell death.
“As a result, chromosomal rearrangements are accumulated in cancer cells, eventually leading to cell death [220].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [220]
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Repair Pathway Choices and Consequences at the Double-Strand Break
Ceccaldi, R., Rondinelli, B., & D’Andrea, A. D. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.07.009 · Cited by 1,499 · see citing works
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445 · see citing works
DNA damage foci: Meaning and significance
Rothkamm, K., Barnard, S. G. R., Moquet, J., Ellender, M., Rana, Z., & Burdak‐Rothkamm, S. (2015) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21944 · Cited by 335 · see citing works
Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer
Borrego‐Soto, G., Ortı́z-López, R., & Rojas‐Martínez, A. (2015) · Genetics and Molecular Biology · doi:10.1590/s1415-475738420150019 · Cited by 320 · see citing works
Essential Roles for Polymerase θ-Mediated End Joining in the Repair of Chromosome Breaks
Wyatt, D. W., Feng, W., Conlin, M. P., Yousefzadeh, M. J., Roberts, S. A., Mieczkowski, P. A., Wood, R. D., Gupta, G. P., & Ramsden, D. A. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.06.020 · Cited by 320 · see citing works
Untangling the roles of TOP2A and TOP2B in transcription and cancer
Uusküla-Reimand, L., & Wilson, M. D. (2022) · Science Advances · doi:10.1126/sciadv.add4920 · Cited by 236 · see citing works
Do DNA Double-Strand Breaks Drive Aging?
White, R. R., & Vijg, J. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.08.004 · Cited by 232 · see citing works
Labarbe, R., Hotoiu, L., Barbier, J., & Favaudon, V. (2020) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2020.06.001 · Cited by 207 · see citing works
Radiobiology of the FLASH effect
Friedl, A. A., Prise, K. M., Butterworth, K. T., Montay‐Gruel, P., & Favaudon, V. (2021) · Medical Physics · doi:10.1002/mp.15184 · Cited by 205 · see citing works
Mode of action-based risk assessment of genotoxic carcinogens
Hartwig, A., Arand, M., Epe, B., Guth, S., Jahnke, G., Lampen, A., Martus, H., Monien, B. H., Rietjens, I. M. C. M., Schmitz‐Spanke, S., et al. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02733-2 · Cited by 205 · see citing works
Kais, Z., Rondinelli, B., Holmes, A. L., O’Leary, C., Kozono, D., D’Andrea, A. D., & Ceccaldi, R. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.031 · Cited by 198 · see citing works
Iliakis, G. E., Murmann-Konda, T., & Soni, A. (2015) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2015.07.001 · Cited by 199 · see citing works
Bacolla, A., Tainer, J. A., Vásquez, K. M., & Cooper, D. N. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw261 · Cited by 164 · see citing works
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications
Shi, R., Liao, C., & Zhang, Q. H. (2021) · Cells · doi:10.3390/cells10030678 · Cited by 148 · see citing works
HELB Is a Feedback Inhibitor of DNA End Resection
Tkáč, J., Xu, G., Adhikary, H., Young, J. T. F., Gallo, D., Escribano‐Diaz, C., Krietsch, J., Orthwein, A., Munro, M., Sol, W., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.013 · Cited by 144 · see citing works
DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP
Deshpande, R. A., Myler, L. R., Soniat, M. M., Makharashvili, N., Lee, L., Lees‐Miller, S. P., Finkelstein, I. J., & Paull, T. T. (2020) · Science Advances · doi:10.1126/sciadv.aay0922 · Cited by 138 · see citing works
The Abscopal Effect of Radiation Therapy
Craig, D. J., Nanavaty, N. S., Devanaboyina, M., Stanbery, L., Hamouda, D., Edelman, G. M., Dworkin, L. D., & Nemunaitis, J. J. (2021) · Future Oncology · doi:10.2217/fon-2020-0994 · Cited by 129 · see citing works
MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
Aparicio, T., Baer, R. J., Gottesman, M. E., & Gautier, J. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201504005 · Cited by 123 · see citing works
Self-citationMCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex
Lee, K. Y., Im, J.-S., Shibata, E., Park, J.-H., Handa, N., Kowalczykowski, S. C., & Dutta, A. (2015) · Nature Communications · doi:10.1038/ncomms8744 · Cited by 112 · see citing works
Vélez-Cruz, R., Manickavinayaham, S., Biswas, A., Clary, R. W., Premkumar, T., Cole, F., & Johnson, D. G. (2016) · Genes & Development · doi:10.1101/gad.288282.116 · Cited by 115 · see citing works
Advances and perspectives of PARP inhibitors
Yi, M., Dong, B., Qin, S., Chu, Q., Wu, K., & Luo, S. (2019) · Experimental Hematology & Oncology · doi:10.1186/s40164-019-0154-9 · Cited by 117 · see citing works
Contributions of DNA Damage to Alzheimer’s Disease
Lin, X., Kapoor, A., Gu, Y., Chow, M. J., Peng, J., Zhao, K., & Tang, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051666 · Cited by 117 · see citing works
Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks
Gürsoy-Yüzügüllü, Ö., House, N. C. M., & Price, B. D. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.11.021 · Cited by 110 · see citing works
Integrating the DNA damage and protein stress responses during cancer development and treatment
Gorgoulis, V. G., Pefani, D., Pateras, I. S., & Trougakos, I. P. (2018) · The Journal of Pathology · doi:10.1002/path.5097 · Cited by 108 · see citing works
A Mechanism to Minimize Errors during Non-homologous End Joining
Stinson, B. M., Moreno, A., Walter, J. C., & Loparo, J. J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.11.018 · Cited by 108 · see citing works
Xu, D., Li, Y., Yin, S., & Huang, F. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00926b · Cited by 108 · see citing works
DNA Damage and Pulmonary Hypertension
Ranchoux, B., Meloche, J., Paulin, R., Boucherat, O., Provencher, S., & Bonnet, S. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060990 · Cited by 105 · see citing works
Dellino, G. I., Palluzzi, F., Chiariello, A. M., Piccioni, R., Bianco, S., Furia, L., Conti, G. D., Bouwman, B. A. M., Melloni, G. E. M., Guido, D., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0421-z · Cited by 104 · see citing works
H. pylori infection alters repair of DNA double-strand breaks via SNHG17
Han, T., Jing, X., Bao, J., Zhao, L., Zhang, A., Miao, R., Guo, H., Zhou, B., Zhang, S., Sun, J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci125581 · Cited by 99 · see citing works
RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks
Lu, H., Shamanna, R. A., Keijzers, G., Anand, R., Rasmussen, L. J., Ćejka, P., Croteau, D. L., & Bohr, V. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.079 · Cited by 95 · see citing works
DNA Polymerase θ: A Unique Multifunctional End-Joining Machine
Black, S., Kashkina, E., Kent, T., & Pomerantz, R. T. (2016) · Genes · doi:10.3390/genes7090067 · Cited by 93 · see citing works
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Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
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Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs
Thapar, R. (2018) · Molecules · doi:10.3390/molecules23112789 · Cited by 83 · see citing works
Ding, X., Cheng, J., Pang, Q., Wei, X., Zhang, X., Wang, P., Yuan, Z., & Qian, D. (2019) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2019.08.009 · Cited by 83 · see citing works
Homeostatic nuclear RAGE–ATM interaction is essential for efficient DNA repair
Kumar, V., Fleming, T. H., Terjung, S., Gorzelanny, C., Gebhardt, C., Agrawal, R., Mall, M. A., Ranzinger, J., Zeier, M. G., Madhusudhan, T., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx705 · Cited by 81 · see citing works
Prophylactic mastectomy for the prevention of breast cancer: Review of the literature
Alaofi, R. K., Nassif, M. O., & Al‐Hajeili, M. (2018) · Avicenna Journal of Medicine · doi:10.4103/ajm.ajm_21_18 · Cited by 78 · see citing works
Role of Akt Activation in PARP Inhibitor Resistance in Cancer
Gallyas, F., Sümegi, B., & Szabó, C. (2020) · Cancers · doi:10.3390/cancers12030532 · Cited by 78 · see citing works
New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer
Han, Y., Yu, X., Li, S., Tian, Y. E., & Liu, C. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.578095 · Cited by 72 · see citing works
Sae2/CtIP prevents R-loop accumulation in eukaryotic cells
Makharashvili, N., Arora, S., Yin, Y., Fu, Q., Wen, X., Lee, J., Kao, C.-H., Leung, J. W. C., Miller, K. M., & Paull, T. T. (2018) · eLife · doi:10.7554/elife.42733 · Cited by 72 · see citing works
Zhao, H. G., Zhuang, Y., Li, R., Liu, Y., Mei, Z., He, Z., Zhou, F., & Zhou, Y. (2018) · Oncology Letters · doi:10.3892/ol.2018.9566 · Cited by 69 · see citing works
Risky 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 · see citing works
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SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability
Chang, Y., Oram, M. K., & Bielinsky, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105391 · Cited by 64 · see citing works
The hidden risks of CRISPR/Cas: structural variations and genome integrity
Aussel, C., Cathomen, T., & Fuster‐García, C. (2025) · Nature Communications · doi:10.1038/s41467-025-62606-z · Cited by 72 · see citing works
Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy
Chen, G., Magis, A. T., Xu, K., Park, D., Yu, D. S., Owonikoko, T. K., Sica, G., Satola, S. W., Ramalingam, S. S., Curran, W. J., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92742 · Cited by 63 · see citing works
Therapeutic Editing of the TP53 Gene: Is CRISPR/Cas9 an Option?
Mirgayazova, R., Khadiullina, R., Chasov, V. V., Mingaleeva, R. N., Рифкатовна, М. Р., Rizvanov, A. A., & Bulatov, E. (2020) · Genes · doi:10.3390/genes11060704 · Cited by 66 · see citing works
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The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
Singh, A. N., Oehler, J., Torrecilla, I., Kilgas, S., Li, S., Vaz, B., Guérillon, C., Fielden, J., Hernández-Carralero, E., Cabrera, E., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2019102361 · Cited by 61 · see citing works
Kostyushev, D. S., Kostyusheva, A., Brezgin, S., Zarifyan, D., Utkina, A., Goptar, I. A., & Chulanov, V. (2019) · Scientific Reports · doi:10.1038/s41598-019-38526-6 · Cited by 62 · see citing works
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Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review)
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Lamin A/C promotes DNA base excision repair
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DNA damage response and repair in ovarian cancer: Potential targets for therapeutic strategies
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Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism
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The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases
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The contribution of DNA repair pathways to genome editing and evolution in filamentous pathogens
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Suppressing Ku70/Ku80 expression elevates homology-directed repair efficiency in primary fibroblasts
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Interplay between Ubiquitin, SUMO, and Poly(ADP-Ribose) in the Cellular Response to Genotoxic Stress
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PLK1 targets CtIP to promote microhomology-mediated end joining
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DNA double-strand break repair: a tale of pathway choices
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Regulatory control of Sgs1 and Dna2 during eukaryotic DNA end resection
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The COP9 signalosome is vital for timely repair of DNA double-strand breaks
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Role of RNF20 in cancer development and progression – a comprehensive review
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The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer
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The Effect of Resveratrol on Cell Viability in the Burkitt’s Lymphoma Cell Line Ramos
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Hallmarks of Cancers: Primary Antibody Deficiency Versus Other Inborn Errors of Immunity
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Phage Mu Gam protein promotes NHEJ in concert with Escherichia coli ligase
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Evolving insights: how DNA repair pathways impact cancer evolution
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Cell resistance to the Cytolethal Distending Toxin involves an association of DNA repair mechanisms
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FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku
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Human RAD50 deficiency: Confirmation of a distinctive phenotype
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Ways of improving precise knock-in by genome-editing technologies
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Strategies for Enhancing the Homology-Directed Repair Efficiency of CRISPR-Cas Systems
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Cell cycle-dependent resolution of DNA double-strand breaks
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BRCA1-A and BRISC: multifunctional molecular machines for ubiquitin signaling
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- Authors
- Aparicio, T., Baer, R., & Gautier, J.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Gautier, Jean
- ORCID
- Gautier, Jean
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 19
- Pages
- 169-175
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC4051845
- OpenAlex
- W2090854519
- Cited by
- 347
- References
- 97
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 27 · 2023: 22 · 2022: 40 · 2021: 36 · 2020: 34 · 2019: 33 · 2018: 39 · 2017: 22 · 2016: 31 · 2015: 26 · 2014: 4
- FWCI
- 11.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA174653, R01CA092245, R01CA167826)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- DNA double-strand break repair, repair pathway choice, genomic instability, cancer susceptibility, BRCA1, BRCA2, chromosomal rearrangements, tumor suppression, carcinogenesis
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, DNA Repair, Humans, Neoplasms, Recombination, Genetic, Signal Transduction, BRCA1 Protein, Genomic Instability, Intracellular Signaling Peptides and Proteins, DNA Breaks, Double-Stranded, DNA End-Joining Repair, Carcinogenesis
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