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Relationship: 1911


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Increase, DNA strand breaks leads to N/A, Inadequate DNA repair

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Oxidative DNA damage leading to chromosomal aberrations and mutations adjacent High Low Carole Yauk (send email) Open for comment. Do not cite EAGMST Under Review
Direct deposition of ionizing energy leading to lung cancer adjacent Moderate Moderate Vinita Chauhan (send email) Under development: Not open for comment. Do not cite EAGMST Under Review

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Unspecific High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

The maintenance of DNA integrity is essential for genomic stability; for this reason cells have multiple response mechanisms that enable the repair of damaged DNA. Thus when DNA double strand breaks (DSBs) occur, the most detrimental type of lesion, the cell will initiate repair machinery. These mechanisms are not foolproof, and emerging evidence suggests that closely spaced lesions can compromise the repair machinery. The two most common DSB repair mechanisms are non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is initiated in G1 and early S phases of the cell cycle (Lieber et al., 2003) and is preferentially used to repair DSB damage (Godwint et al., 1994), as it is rapid and more efficient than HR (Lliakis, 1991; Jeggo, 1998; Mao et al., 2008). In higher-order eukaryotes such as humans, NHEJ is the favoured DNA repair mechanism because of the large non-coding regions within the genome. NHEJ can occur through one of two subtypes: canonical NHEJ (C‐NHEJ) or alternative non-homologous end joining (alt-NHEJ). C-NHEJ, as the name suggests, simply ligates the broken ends back together. In contrast, alt‐NHEJ occurs when one strand of the DNA on either side of the break is resected to repair the lesion (Bétermier et al., 2014). Both repair mechanisms are error‐prone, meaning insertions and deletions are sometimes formed due to the DSBs being repaired imperfectly (Thurtle-Schmidt and Lo, 2018). However, alt-NHEJ is considered more error-prone than C-NHEJ, as studies have shown that it more often leads to chromosomal aberrations (Zhu et al., 2002; Guirouilh-Barbat et al., 2007; Simsek & Jasin, 2010).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

The biological rationale linking increased DNA DSB formation with inadequate DSB repair is supported strongly by literature. This is evident from the number of review articles that have been published on the subject. Of particular relevance is a recent review which focussed particularly on DSBs induced by ionizing radiation and extensively detailed the processes involved in repairing DSBs, including discussions of entire pathways and individual proteins involved in DNA repair (Thompson, 2012). Multiple other shorter reviews are also available on the subject, which cover such topics as: the mechanisms of DSB formation and repair, how to quantify these two events, and the biological consequences of unrepaired or misrepaired DNA damage (van Gent et al., 2001; Khanna & Jackson, 2001; Vignard et al., 2013; Moore et al., 2014; Rothkamm et al., 2015; Chang et al., 2017; Sage and Shikazono, 2017). A brief overview of the biological plausibility of this KER is given below; for more detail, please consult the above-cited reviews.

NHEJ is commonly used in repairing DSBs in multicellular eukaryotic organisms, especially in humans (Feldmann et al., 2000).  Due to being inherently error-prone, this repair process is used to generate genetic variation within antigen receptor axons through VDJ recombination, a process that leads to the careful breakage and repair of DNA (Murakami & Keeney, 2008; Malu et al., 2012).  Genetic variation is also often generated during the repair of highly toxic DSB lesions. Repair to these DSB sites normally triggers cell cycle delay. NHEJ is most active in the following order of the cell cycle: G1 > S > G2/M (Mao et al., 2008). Since most somatic mammalian cells are in the G1 pre-replicative phase, DSBs also usually appear in this phase and thus are often repaired using the error-prone NHEJ (Jeggo et al., 1995).

The two broken ends of DNA DSBs are bridged by overlapping single-strand microhomology termini (Anderson, 1993; Getts & Stamato, 1994; Rathmell & Chu, 1994; Jeggo et al., 1995; Miller et al., 1995; Kirchgessner et al., 1995). The microhomology termini are ligated only when complementary base pairs are overlapped and, depending on where this match is found on the termini, it can lead to deletions and other rearrangements. With increasing DSBs, the probability of insufficient or incorrect repair of these breaks increases proportionately. It has been suggested that clustered DNA damage is less easily repairable than any other form of DNA damage (United Nations, 2000).  With multiple lesions in close proximity within a damaged cluster, the probability of misrepair is high. This leads to an increased number of misrepaired termini (Goodhead et al., 1994; Goodhead, 1980), as the presence of multiple damage sites interferes with the ability of the repair enzymes to recognize and bind to the DNA accurately (Harrison et al., 1999).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Uncertainties and inconsistencies in this KER are as follows:

  1. There is controversy surrounding how error-prone NHEJ truly is.  Recent studies suggest that the process may be quite accurate (reviewed in (Bétermier et al. 2014)). The accuracy of NHEJ may actually be dependent on the structure of the termini. Thus, the termini processing rather than the NHEJ mechanism itself is argued to be the error-prone process (Bétermier et al. 2014).
  2. There may be different cellular responses associated with low-dose radiation exposure and high-dose radiation exposure; these differences may also be dependent on a DSB threshold being exceeded prior to initiation repair. It has been suggested that DNA repair may not be activated at low doses of radiation exposure in order to prevent the risk of mutations from error-prone repair mechanisms (Marples 2004).
  3. DSB repair fidelity varies in terms of confounding factors and the genetic characteristics of individuals (Scott 2006). For example, individuals who smoke have a 50% reduction in the mean level of DSB repair capacity relative to the non-smokers; this is due to an increased methylation index in smokers. A higher methylation index indicates more inactivation of gene expression. It is thus possible that expression of DNA repair proteins in smokers is decreased due to increased methylation of the genes encoding for repair proteins. In terms of individual genetics, single nucleotide polymorphisms (SNPs) within the MRE11A, CHEK2, XRCC3, DNA-PKcs, and NBN repair genes have been highly associated with the methylation index (Leng et al. 2008). SNPs can critically affect the function of these core proteins, varying the fidelity of DNA repair from person to person.
  4.  Cells containing DNA damaged may be eliminated by apoptotic pathways, therefore not undergo repair, alternatively evidence has also shown that damaged cells can propagate due to lack of detection by repair machinery (Valentin 2005).  
Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

There is evidence of a response-response relationship for DNA repair of radiation-induced DSBs. The frequency of DSBs has been shown to increase linearly with radiation dose (Lobrich et al., 2000; Rothkamm & Lo, 2003; Kuhne et al., 2005; Asaithamby & Chen, 2009). For DNA repair, increasing doses of a radiation stressor were found to cause a linear-quadratic relationship between the radiation dose and the number of misrejoined DSBs per cell (Kuhne et al., 2005). Interestingly, the relationships between radiation and DNA repair were found to vary depending on the type of radiation. There was a more linear response between radiation dose and the number of misrejoined DSBs for high LET particles relative to a more curvilinear relationship for lower LET particles (Rydberg et al., 2005). Additionally, a linear relationship was defined for low dose-rate radiation and the number of non-repaired DNA DSBs, but a linear-quadratic equation was described for high dose-rate radiation (Dikomey & Brammer, 2000).

This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

Data from temporal response studies suggests that DSB repair may occur within 15 - 30 minutes of a DSB-inducing radiation stressor (Paull et al., 2000; Rothkamm & Lo, 2003; Pinto & Prise, 2005; Dong et al., 2017), with foci documented as early as 3-5 minutes post-irradiation (Asaithamby & Chen, 2009). The majority of DSB repair has been reported to occur within the first 3 - 6 hours following DSB induction (Rothkamm & Lo, 2003; Pinto & Prise, 2005; Asaithamby & Chen, 2009; Dong et al., 2017), with complete or near-complete DSB repair within 24 hours of the radiation stressor (Dikomey & Brammer, 2000; Lobrich et al., 2000; Rothkamm & Lo, 2003; Asaithamby & Chen, 2009; Mcmahon et al., 2016).  In one 48-hour time-course experiment for DSB repair using two different types of radiation, the following repair progression was found at 30 minutes, 1 hour, 3 hours, 24 hours and 48 hours, respectively: 40 - 55%, 55 - 70%, 85%, 97 - 98% and 98% repair for X-rays and 30%, 45 - 50%, 65 - 70%, 85 - 90% and 90 - 96% repair for alpha particles (Pinto & Prise, 2005). Twenty-four hours post-irradiation, the frequency of DSB misrejoining was found to remain constant at approximately 80% for the 10 days that the DSB repair was monitored (Kuhne et al., 2000).

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

Not identified.

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Not identified.

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

The domain of applicability is multicellular eukaryotes (Lieber, 2008; Hartlerode & Scully, 2009) , plants (Gorbunova, 1997; Puchta, 2005), certain strains of bacteria such as Mycobacteria, PseudomonasBacillus and Agrobacterium (Shuman & Glickman, 2007), and yeast (Wilson & Lieber, 1999).


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Anderson, C.W. 1993, "DNA damage and the DNA-activated protein kinase.", Trends Biochem. Sci. 18(11):433–437. doi:10.1016/0968-0004(93)90144-C.

Antonelli, A.F. et al. (2015), "Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation: Relationship with Early and Delayed Reproductive Cell Death", Radiat. Res. 183(4):417-31, doi:10.1667/RR13855.1.

Asaithamby, A. & D.J. Chen (2009), "Cellular responses to DNA double-strand breaks after low-dose c-irradiation.", Nucleic Acids Res. 37(12):3912–3923. doi:10.1093/nar/gkp237.

Bétermier, M., P. Bertrand & B.S. Lopez (2014), "Is Non-Homologous End-Joining Really an Inherently Error-Prone Process?", PLoS Genet. 10(1). doi:10.1371/journal.pgen.1004086.

Bracalente, C. et al. (2013), "Induction and Persistence of Large g H2AX Foci by High Linear Energy Transfer Radiation in DNA-Dependent protein kinase e Deficient Cells.", Int. J. Radiat. Oncol. Biol. Phys. 87(4). doi:10.1016/j.ijrobp.2013.07.014.

Chang, H.H.Y. et al. (2017), "Non-homologous DNA end joining and alternative pathways to double ‑ strand break repair.", Nat. Publ. Gr. 18(8):495–506. doi:10.1038/nrm.2017.48.

Dikomey, E. & I. Brammer (2000), "Relationship between cellular radiosensitivity and non-repaired double-strand breaks studied for di Ú erent growth states, dose rates and plating conditions in a normal human broblast line.", Int. J. Radiat. Biol., 76(6). doi:10.1080/09553000050028922.

Dong, J. et al. (2017), "Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.", Oncotarget.  8(14):22662–22673. doi: 10.18632/oncotarget.15153.

Dubrova, Y.E. et al. (2002), "Elevated Minisatellite Mutation Rate in the Post-Chernobyl Families from Ukraine.", Am. J. Hum. Genet. 71(4):801–809. doi:10.1086/342729.

Feldmann, E. et al. (2000), "DNA double-strand break repair in cell-free extracts from Ku80-deficient cells: implications for Ku serving as an alignment factor in non-homologous DNA end joining.", Nucleic Acids Res. 28(13):2585–2596. doi:10.1093/nar/28.13.2585.

van Gent D.C., J.H.J. Hoeijmakers & R. Kanaar (2001), "Chromosomal stability and the DNA double-stranded break connection.", Nat. Rev. Genet. 2(3):196–206. doi:10.1038/35056049.

Getts, R.C. & T.D. Stamato (1994), "Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant.", J. Biol. Chem. 269(23):15981–15984. 

Godwin, A.R. et al. (1994), "Spontaneous and restriction enzyme-induced chromosomal recombination in mammalian cells.", PNAS 91(December):12554–12558. doi: 10.1073/pnas.91.26.12554

Goodhead, D.T. (1994), "Initial events in the cellular effects of ionizing radiations: clustered damage in DNA.", Int. J. Radiat. Biol. 65(1):7–17. doi:10.1080/09553009414550021.

Goodhead, D.T. et al. (1980), "Mutation and inactivation of cultured mammalian cells exposed to beams of accelerated heavy ions. IV. Biophysical interpretation.", Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 37(2):135–67. doi:10.1080/09553008014550201.

Gorbunova, V. 1997, "Non-homologous DNA end joining in plant cells is associated with deletions and filler DNA insertions.", Nucleic Acids Res. 25(22):4650–4657. doi:10.1093/nar/25.22.4650.

Guirouilh-Barbat, J. et al. (2007), "Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends.", Proc Natl Acad Sci. 104(52):20902–20907. doi:10.1073/pnas.0708541104.

Grudzenski, S. et al. (2010), "Inducible response required for repair of low-dose radiation damage in human fibroblasts.", Proc. Natl. Acad. Sci. USA. 107(32): 14205-14210, doi:10.1073/pnas.1002213107.

Guirouilh-barbat, J. et al. (2014), "Is homologous recombination really an error-free process?", Front Genet. 5:175. doi:10.3389/fgene.2014.00175.

Harrison, L., Z. Hatahet & S.S. Wallace (1999), "In vitro repair of synthetic ionizing radiation-induced multiply damaged DNA sites 1 1Edited by J. H. Miller.", J. Mol. Biol. 290(3):667–684. doi:10.1006/jmbi.1999.2892.

Hartlerode, A.J. & R. Scully (2009), "Mechanisms of double-strand break in somatic mammalian cells.", Biochem J. 423(2):157–168. doi:10.1042/BJ20090942.Mechanisms.

Jeggo, P.A. (1998), "DNA breakage and repair.", Adv. Genet. 38:185–218. doi:DOI: 10.1016/S0065-2660(08)60144-3. doi: DOI: 10.1016/S0065-2660(08)60144-3.

Khanna, K.K. & S.P. Jackson (2001), "DNA double-strand breaks: signaling , repair and the cancer connection.", 27(march):247–254. doi: 10.1038/85798.

Kirchgessner, C. et al. (1995), "DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect.", Science (80- ). 267(5201):1178–1183. doi:10.1126/science.7855601.

Kuhne, M., K. Rothkamm & M. Lobrich (2000), "No dose-dependence of DNA double-strand break misrejoining following a -particle irradiation.", Int. J. Radiat. Biol. 76(7):891-900

Kuhne, M., G. Urban & M. Lo (2005), "DNA Double-Strand Break Misrejoining after Exposure of Primary Human Fibroblasts to CK Characteristic X Rays, 29 kVp X Rays and 60Co γ Rays", Radiat. Res., 164(5):669–676. doi:10.1667/RR3461.1.

de Lara, C.M. et al. (2001), "Dependence of the Yield of DNA Double-Strand Breaks in Chinese Hamster V79-4 Cells on the Photon Energy of Ultrasoft X Rays.", Radiation Research. 155(3):440-8. doi:10.1667/0033-7587(2001)155[0440:DOTYOD]2.0.CO;2.

Leng, S. et al. (2008), "Public Access NIH Public Access. PLoS One.", 32(7):736–740. doi:10.1371/journal.pone.0178059.

Lieber, M.R. (2008), "The mechanism of human nonhomologous DNA End joining.", J Biol Chem. 283(1):1–5. doi:10.1074/jbc.R700039200.

Lobrich, M. et al. (2000), "Joining of Correct and Incorrect DNA Double-Strand Break Ends in Normal Human and Ataxia Telangiectasia Fibroblasts.", 68(July 1999):59–68. doi:DOI: 10.1002/(SICI)1098-2264(200001)27:1<59::AID-GCC8>3.0.CO;2-9.

Lobrich, M. et al. (2005), "In vivo formation and repair of DNA double-strand breaks after computed tomography examinations.", Proc. Natl. Acad. Sci. 102(25):8984–8989. doi:10.1073/pnas.0501895102.

Malu, S. et al. (2012), "Role of non-homologous end joining in V(D)J recombination.", Immunol. Res. 54(1–3):233–246. doi:10.1007/s12026-012-8329-z.

Mao, Z. et al. (2008), "DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells.", Cell Cycle. 7(18):2902–2906. doi:10.4161/cc.7.18.6679.

Marples, B. (2004), "Is low-dose hyper-radiosensitivity a measure of G2-phase cell radiosensitivity?", Cancer Metastasis Rev. 23(3–4):197–207. doi:10.1023/B:CANC.0000031761.61361.2a.

McMahon, S.J. et al. (2016), "Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.", Nat. Publ. Gr.(April):1–14. doi:10.1038/srep33290.

Miller, R.C. et al. (1995), "The Biological Effectiveness of Radon-Progeny Alpha Particles.", Radiat. Res. 142(1):61–69. doi:10.2307/3578967.

Moore, S., F.K.T. Stanley & A.A. Goodarzi (2014), "The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation – No simple task.", DNA repair (Amst), 17:64–73. doi: 10.1016/j.dnarep.2014.01.014.

Murakami, H. & S. Keeney (2008), "Regulating the formation of DNA double-strand breaks in meiosis.", Genes Dev. 22(3):286–292. doi:10.1101/gad.1642308.

Paull, T.T. et al. (2000), "A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.", Curr. Biol. 10(15):886–895. doi:10.1016/S0960-9822(00)00610-2

Pinto, M. & K. Prise (2005), "Evidence for Complexity at the Nanometer Scale of Radiation-Induced DNA DSBs as a Determinant of Rejoining Kinetics Evidence for Complexity at the Nanometer Scale of Radiation-Induced DNA DSBs as a Determinant of Rejoining Kinetics.", Radiat. Res. 164(1):73-85  doi:10.1667/RR3394.

Puchta, H. (2005), "The repair of double-strand breaks in plants: Mechanisms and consequences for genome evolution.", J. Exp. Bot. 56(409):1–14. doi:10.1093/jxb/eri025.

Thurtle-Schmidt, D.M. & T-W. Lo (2018), "Molecular biology at the cutting edge: A review on CRISPR/CAS9 gene editing for undergraduates.", Biochem. Mol. Biol. Educ. 46(2):195–205. doi:10.1002/bmb.21108.

Rathmell, W,K. & G. Chu (1994), "Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks.", Proc. Natl. Acad. Sci. 91(16):7623–7627. doi:10.1073/pnas.91.16.7623.

Rogakou, E.P. et al. (1999), "Megabase Chromatin Domains Involved in DNA Double-Strand Breaks In Vivo.", J. Cell Biol, 146(5):905-16. doi: 10.1083/jcb.146.5.905.

Rothkamm, K. et al. (2015), "Review DNA Damage Foci: Meaning and Significance.", Environ. Mol. Mutagen., 56(6):491-504, doi: 10.1002/em.21944.

Rothkamm, K. & M. Lo (2003), "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.", PNAS, 100(9):5057-62. doi:10.1073/pnas.0830918100.

Rube, C.E. et al. (2008), "Cancer Therapy: Preclinical DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing.", Clin. Cancer Res., 14(20):6546–6556. doi:10.1158/1078-0432.CCR-07-5147.

Rydberg, B. et al. (2005), "Dose-Dependent Misrejoining of Radiation-Induced DNA Double-Strand Breaks in Human Fibroblasts: Experimental and Theoretical Study for High- and Low-LET Radiation.", Radiat. Res. 163(5):526–534. doi:10.1667/RR3346.

Sage, E. & N. Shikazono (2017), "Free Radical Biology and Medicine Radiation-induced clustered DNA lesions: Repair and mutagenesis.", Free. Radic. Biol. Med. 107(December 2016):125–135. doi:10.1016/j.freeradbiomed.2016.12.008.

Scott, B. (2006), "Stochastic Thresholds: A Novel Explanation of Nonlinear Dose-Response Relationships for Stochastic Radiobiological Effects.", Dose-Response, 3(4):547–567. doi:10.2203/dose-response.003.04.009.

Shuman, S. & M.S. Glickman (2007), "Bacterial DNA repair by non-homologous end joining.", Nat. Rev. Microbiol. 5(11):852–861. doi:10.1038/nrmicro1768.

Simsek, D. & M. Jasin (2010), "HHS Public Access.", 118(24):6072–6078. doi:10.1002/cncr.27633.

Sutherland, B.M. et al. (2000), "Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation.", J. of Rad. Res. 43 Suppl(S):S149-52. doi: 10.1269/jrr.43.S149

Thompson, L.H. (2012), "Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells : The molecular choreography.", Mutat Res., 751(2):158–246. doi: 10.1016/j.mrrev.2012.06.002.

Valentin J. (2005), "Low-dose Extrapolation of Radiation-related Cancer Risk.", Ann. ICRP, 35(4):1-140

Vignard, J., G. Mirey & B. Salles (2013), "Ionizing-radiation induced DNA double-strand breaks: A direct and indirect lighting up.", Radiother. Oncol. 108(3):362–369. doi:10.1016/j.radonc.2013.06.013.

Ward, J. F. (1988), "DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability.", Prog. Nucleic Acid Res. Mol. Biol. 35(C):95–125. doi:10.1016/S0079-6603(08)60611-X.

Wilson, T.E. & M.R. Lieber (1999), "Efficient Processing of DNA Ends during Yeast Nonhomologous End Joining.", J. Biol. Chem. 274(33):23599–23609. doi:10.1074/jbc.274.33.23599.

Zhu, C. et al. (2002), "Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.", Cell. 109(7):811–21. doi:10.1016/s0092-8674(02)00770-5.