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Relationship: 1911


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, DNA strand breaks leads to Inadequate DNA repair

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). 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

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 Brendan Ferreri-Hanberry (send email) Open for comment. Do not cite WPHA/WNT Endorsed
Deposition of energy leading to lung cancer adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts adjacent Moderate Moderate Arthur Author (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) 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.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. 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). The latter predominates in stem cells as they are frequently in the replicative phase of the cell cycle (Choi et al., 2020). 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. However, when other repair mechanisms (e.g., NHEJ, HR) are compromised, single strand annealing, which is a low fidelity mechanism may be involved (Chang et al., 2017). 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). All repair mechanisms are error‐prone, meaning that 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). HR is operative during late S and G2 phases where the sister chromatid can be used as template for error-free repair (Van Gent et al 2001). Because of the reliance on the undamaged sister chromatid to repair the DSB, HR is less error-prone than NEHJ. Nevertheless, defects in HR are known to contribute to genomic instability and the formation of chromosomal aberrations (Deans et al 2000)

There is extensive evidence that DNA repair capacity can be overwhelmed or saturated in the presence of high numbers of strand breaks. For example, with multiple single strand breaks (SSBs) in close proximity that can lead to DSBs (Caldecott, 2024). This is demonstrated by decades of studies showing dose-related increases in chromosomal exchanges, chromosomal breaks and micronuclei following exposure to double-strand break inducers. Additionally, the loss of heterozygosity (LOH)  is an example of how during the repair of incorrect DNA that uses HR, there may be a loss of an allele during repair (Smukowski et al., 2023). Inadequate repair not only refers to overwhelming of DNA repair machinery, but also the use of repair mechanisms that are error-prone (i.e., misrepair is considered inadequate repair).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field 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.   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 that focuses particularly on DSBs induced by ionizing radiation and extensively details 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 (Lett, 1996; van Gent et al., 2001; Khanna & Jackson, 2001; Vignard et al., 2013; Moore et al., 2014; Rothkamm et al., 2015; Chang et al., 2017; Löbrich and Jeggo, 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.

When confronted with DSBs, there are two common repair pathways employed by the cell: homologous recombination (HR) and non-homologous end-joining (NHEJ). In HR, a homologous sequence on a sister chromatid is used as a template, ensuring that no sequence information is lost over the course of repair (e.g., Ferguson & Alt, 2001; van Gent et al., 2001; Jeggo & Markus, 2015; Schipler & Iliakis, 2013). Due to being inherently error-prone, 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). Cells in other phases of the cell cycle (S or G2) use HR (Ceccaldi et al., 2016). In addition,) and damaged cells in G0 also appear to use NHEJ repair (Frock et al., 2021).

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; Stenerlöw et al., 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; Tsao, 2007; Blakely, 2012), 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; Tsao, 2007).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and inconsistencies in this KER are as follows:

  • 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).
  • 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).
  • 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.
  •  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).  
  • The focus of this KER was on DSBs because there is lack of data to support that SSBs lead to inadequate repair. Multiple SSBs can lead to DSBs. Thus, DSBs are the focus as they can drive the cell towards genomic instability, apoptosis or tumorigenesis. Further quantitative evidence to define the extent of SSBs leading to DSBs and the relationship with repair is necessary.
  • Ercc2+/- mice have a mutation in a gene involved in the nucleotide excision repair (NER) pathway, leading to DNA repair deficiency. However, when compared to wild type mice Ercc2+/- mice had fewer DNA strand breaks. This was true of both central and peripheral lens cells, as well as 4 and 24 h after irradiation (60Co γ-rays, 0.3, 0.063 Gy/min) (Barnard et al., 2021).
  • DNA damage repair times can vary depending on the stressors that instigate the DNA damage. For example, it has been found that some types of radiation i.e., high linear energy transfer (LET) increases the amount of time required to repair DNA breaks (Aufderheide, 1987; Frankenburg-Schwager et al., 1994; Rydberg et al., 1994; Baumstark-Khan et al., 2003; Tsao, 2007; Blakely, 2012), however Stenerlöw et al. (2000) found that repair half-times were independent of LET.  

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating Factor 


Effects on the KER  


Linear energy transfer (LET) 

Increased LET 

As the LET of the stressor increases, the amount of misrepaired and unrejoined DSBs also increases. One possible explanation for this is that DSB free ends are closer together at higher LETs, making it easier for misrepair to occur. Furthermore, higher LET stressors produce more complex, clustered breaks which also increasing repair difficulty. At very high LET values (over 10 000 keV/um), no significant DNA repair is detected. 

Aufderheide, 1987; Rydberg et al., 1994; Durante et al., 1998; Kuhne et al., 2000; Stenerlöw et al., 2000; Baumstark-Khan et al., 2003; Tsao, 2007; Mukherjee et al., 2008; Blakely, 2012; Hamada, 2017 


Decreased oxygen levels  

Cells in an anoxic environment will rejoin DNA breaks more quickly than those in an oxic environment because oxygen can attach to the broken ends of DNA, fixing the damage and making it unrepairable. 

Frankenburg-Schwager et al., 1994 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  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 (Löbrich 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).

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?). 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 Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not identified.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from in vivo adult mice with no specification on sex, and in vitro human models that do not specify sex. 


List of the literature that was cited for this KER description. 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.

Aufderheide, E. (1987), “Heavy ion effects on cellular DNA: strand break induction and repair in cultured diploid lens epithelial cells”, International journal of radiation biology and related studies in physics, chemistry and medicine, Vol. 51/5, Taylor & Francis, London, 

Barnard, S. G. R. (2018), “Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage”, International Journal of Radiation Biology, Vol. 94/12, 

Barnard, S. G. R. (2021), “Radiation-induced DNA damage and repair in lens epithelial cells of both Ptch1(+/-) and Ercc2(+/-) mutated mice”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, 

Baumstark-Khan, C. et al. (2003), “Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation”, Advances in Space Research, Vol. 31/6, Elsevier Ltd, England, 

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.

Blakely, E. A. (2012), “Lauriston S. Taylor lecture on radiation protection and measurements: what makes particle radiation so effective?”, Health Physics, Vol. 103/5, Health Physics Society, United States, 

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.

Caldecott K. W. (2024). “Causes and consequences of DNA single-strand breaks”. Trends in biochemical sciences, 49(1), 68–78.    

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.

Choi, E. H., Yoon, S., Koh, Y. E., Seo, Y. J., & Kim, K. P. (2020),. “Maintenance of genome integrity and active homologous recombination in embryonic stem cells”,. Experimental & molecular medicine, 52(8), 1220–1229. 

Coquerelle, T. M., K. F. Weibezahn and C. Lücke-Huhle (1987), “Rejoining of double strand breaks in normal human and ataxia-telangiectasia fibroblasts after exposure to 60Co gamma-rays, 241Am alpha-particles or bleomycin”, International journal of radiation biology and related studies in physics, chemistry, and medicine, Vol. 51/2,

Deans, B., Griffin, C. S., Maconochie, M. & Thacker, J. (2000), Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J. 19, 6675–6685.

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.

Durante, M. et al. (1998), “Rejoining and misrejoining of radiation-induced chromatin breaks. IV. Charged particles”, Radiation Research, Vol. 149/5, Radiation Research Society, Oak Brook, 

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.

Ferguson, D.O. & F.W. Alt (2001), "DNA double strand break repair and chromosomal translocation: Lessons from animal models.", Oncogene, 20(40):5572–5579. doi: 10.1038/sj.onc.1204767.

Frankenburg-Schwager, M. et al. (1994), “Half-life values for DNA double-strand break rejoining in yeast can vary by more than an order of magnitude depending on the irradiation conditions”, International Journal of Radiation Biology, Vol. 66/5, Informa UK Ltd, London, 

Frock, R. L., Sadeghi, C., Meng, J., & Wang, J. L. (2021),. “DNA End Joining: G0-ing to the Core”,. Biomolecules, 11(10), 1487.  

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.

Hamada, N. (2017), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International Journal of Radiation Biology, Vol. 93/10, Taylor & Francis, England, 

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.

Jeggo, P.A. & L. Markus (2015), "How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability.", Biochem. J., 471(1):1–11. doi:10.1042/BJ20150582.

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.

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. 

Kuhne, M., K. Rothkamm & M. Löbrich (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.

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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. and P. Jeggo, (2017), A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis., Trends Biochem Sci. 42(9): 690-701. doi: 10.1016/j.tibs.2017.06.011.

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.

Lett, J. T. (1996), “Experimental models for cellular radiation targets: LET, RBE and radioprotectors”, Advances in Space Research, Vol. 18/1, Elsevier Ltd, England, 

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.

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