This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1912


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

Inadequate DNA repair leads to Increase, Chromosomal aberrations

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 Do not cite WPHA/WNT Endorsed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 High Low Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts adjacent Low Low 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
rat Rattus norvegicus Low NCBI
mouse Mus musculus Low NCBI
human Homo sapiens Low NCBI

Sex Applicability

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

Life Stage Applicability

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

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

Cells are exposed to many insults, both endogenous and exogenous, that may cause damage to their DNA. In response to this constant threat, cells have accordingly evolved many different pathways for repairing DNA damage (Pfeiffer & Goedecke, 2000; Hoeijmakers, 2001; Jeggo & Markus, 2015; Rode et al., 2016). When confronted with double strand breaks (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 the sister chromatid is used as a template, ensuring that no sequence information is lost over the course of repair (Ferguson & Alt, 2001; van Gent et al., 2001; Hoeijmakers, 2001; Jeggo & Markus, 2015; Schipler & Iliakis, 2013; Venkitaraman, 2002). However, this method of DNA repair may result in a loss of an allele leading to heterozygosity. This may occur if a non-homologous chromosome with an erronous sequence is used as the template instead of the homologous chromosome, thus leading to a loss of genetic information (Ferguson & Alt, 2001). Despite this possible error, HR is generally considered to be one of the more accurate methods of DNA repair because it does make use of a template (van Gent et al., 2001; Schipler & Iliakis, 2013; Venkitaraman, 2002) .  NHEJ, however, does not use a template and is generally described as being error-prone. This repair process allows for the direct religation of broken DNA ends without using template DNA as a guide (van Gent et al., 2001; Ferguson & Alt, 2001; Hoeijmakers, 2001; Venkitaraman, 2002; Schipler & Iliakis, 2013; Jeggo & Markus, 2015; Rode et al., 2016). In lieu of a template, NHEJ utilizes rapid repair kinetics to relegate the broken ends before they have time to diffuse away from each other (Schipler & Iliakis, 2013), thus fitting two ‘sticky’ DNA ends back together (Danford, 2012). There is not, however, an inherent quality control check; as such, sections of DNA may be gained or lost, or the wrong ends may be rejoined (Schipler & Iliakis, 2013). There are two versions of this error-prone DNA repair: classical or canonical NHEJ (c-NHEJ), and alternative NHEJ (alt-NHEJ) (Schipler & Iliakis, 2013). It is not well understood when or why one pathway is selected over another (Venkitaraman, 2002; Schipler & Iliakis, 2013). It has been proposed that the phase of the cell cycle may influence repair pathway choice (Ferguson & Alt, 2001; Vodicka et al., 2018); for instance, HR is generally more common than NHEJ when sister chromatids are available in S and G2 phases of the cell cycle (Hoeijmakers, 2001; Venkitaraman, 2002). If both HR and c-NHEJ are compromised, alt-NHEJ, which is slower and more error-prone than c-NHEJ, is thought to be the stand-by repair mechanism (Schipler & Iliakis, 2013). As BRCA2 is involved in both the NHEJ and HR repair pathways, it has recently been observed in BRCA2 deficient cells that single-strand annealing (SSA) may be triggered (Han et al. 2017).

If these repair processes are not able to properly and adequately repair the DNA, this may lead to the formation of chromosomal aberrations (CAs). CAs are defined as abnormalities in the chromosome structure, often due to losses or gains of chromosome sections or the entire chromosomes itself (van Gent et al., 2001; Durante & Cucinotta, 2008). These abnormalities can take many different forms and can be classified according to several different schemes. CAs can be defined as breaks, which occur when DSBs are not rejoined, or as exchanges, where the presence of multiple DSBs results in misrejoining of the DNA ends (Danford, 2012; Registre et al., 2016). CA classes can be further subdivided into chromosome-type aberrations (CSAs) that affect both sister chromatids, and chromatid-type aberrations (CTAs), affecting only one chromatid (Danford, 2012) . Examples of CSAs include chromosome-type breaks, centric ring chromosomes, and dicentric chromosomes (which have two centromeres), while CTAs refer to chromatid-type breaks and chromatid exchanges (Hagmar et al., 2004; Bonassi et al., 2008). Other types of CAs that may occur include micronuclei (MN; small nucleus-like structures containing chromosome fragments enclosed by a nuclear membrane (Fenech & Natarajan, 2011; Doherty et al., 2016)), nucleoplasmic bridges (NPBs; a stretch of chromatin enclosed by a nuclear membrane that is attached to two centromeres (Fenech & Natarajan, 2011; Russo et al., 2015)), nuclear buds (NBUDs; a MN that is still connected to the nucleus by nucleoplasmic material (Fenech & Natarajan, 2011)), and copy number variants (CNVs;  base pair to megabase pair deletions or duplications of chromosomal segments (Russo et al., 2015)). CAs may also be classified as stable aberrations (translocations, inversions, insertions and deletions) and unstable aberrations (dicentric chromosomes, acentric fragments, centric rings and MN) (Hunter & Muirhead, 2009; Qian et al., 2016). 

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

Overall Weight of Evidence: Low 

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

There is strong biological plausibility for a relationship between inadequate repair of DNA damage and a corresponding increase in CAs. This is evident in a variety of reviews on the topic (van Gent et al., 2001; Hoeijmakers, 2001; Povirk, 2006; Weinstock et al., 2006; Lieber et al., 2010; Rode et al., 2016).

The two most common methods used to repair DSBs, which are one of the most dangerous types of DNA lesions, are HR and NHEJ. Mechanisms for these two methods of DNA repair are well-established and have been thoroughly reviewed (Van Gent et al. 2001; Hoeijmakers 2001; Lieber et al. 2010; Jeggo and Markus 2015; Sishc and Davis 2017). Briefly, HR requires a template DNA strand to repair damage and thus facilitates the invasion of the damaged strand with matching sequences on homologous chromosomes or sister chromatids (Ferguson and Alt 2001; van Gent et al. 2001; Hoeijmakers 2001; Jeggo and Markus 2015; Schipler and Iliakis 2013; Venkitaraman 2002). Proteins involved in the HR pathway include the RAD50 proteins, MRE11, BRCA1, and BRCA2 (Ferguson and Alt 2001; van Gent et al. 2001; Hoeijmakers 2001; Jeggo and Markus 2015; Venkitaraman 2002). In contrast to this relatively accurate form of DNA repair ( van Gent et al. 2001; Schipler and Iliakis 2013; Venkitaraman 2002), NHEJ is more error-prone. It does not require a template to guide repair, but simply re-ligates broken DNA ends back together (Van Gent et al. 2001; Ferguson and Alt 2001; Hoeijmakers 2001; Lieber et al. 2010; Schipler and Iliakis 2013; Jeggo and Markus 2015; Rode et al. 2016; Sishc and Davis 2017) Proteins used during NHEJ include the DNA-PK complex (encompassing Ku70, Ku80 and DNA-PKcs), and the XRCC4-DNA ligase IV complex (Ferguson & Alt, 2001; van Gent et al., 2001; Hoeijmakers, 2001; Jeggo & Markus, 2015; Sishc & Davis, 2017).Interestingly, NHEJ is used in the biological V(D)J recombination process because its error-prone mechanism allows immune cells to develop a wide range of unique receptors for antigen detection (Ferguson & Alt, 2001; van Gent et al., 2001; Lieber, 2010).     

Damaged DNA in the form of DSBs can follow  three possible outcomes: the DSB is rejoined accurately, with no changes made to the genome; the DSB is left unrepaired and the broken ends diffuse away from each other; or the DSB is repaired incorrectly such that the repaired version is different from the original version (Danford, 2012). These latter two errors in repair (the complete absence of repair or inaccurate repair) could arise due to interruptions to the repair process that allow time for the broken ends to move away from each other before they can be rejoined, mis-rejoining of the wrong DNA ends, or post-repair alterations that modify the junction point and lead to nucleotide losses (Schipler and Iliakis 2013). Unrepaired DSBs are the direct origin of micronuclei and unrepaired chromosomes correlated with radiosensitivity (Foray et al., 2016). Errors occurring during repair may be particularly detrimental if they interrupt or modify key genes, or if chromosome structures are created that cannot undergo proper mitosis (Schipler and Iliakis 2013).

The classic model of CA formation has centered around misrepair of DSBs. Exposing DNA to an endogenous or exogenous DSB-inducing agent directly results in DSBs, which may either persist or be misrepaired by inadequate repair mechanisms; in the event of this erroneous repair, CAs often eventually result (Bignold, 2009; Danford, 2012; Schipler & Iliakis, 2013) . Another model has been proposed that suggests CAs may actually be due to failure of enzymes that tether the DNA strands during the repair of enzyme-induced breaks in the DNA; the various pathways in the cell would likely employ assorted tethering enzymes. The numerous types of CAs would thus result from different kinds of tethering errors (Bignold 2009).

The type of CA that results may be dependent on the timing of inadequate repair. For example, DSBs may result in CSAs or CTAs depending on when during the cell cycle the DSB was incurred. DSBs that are not repaired before DNA duplication in the S-phase will be replicated and result in CTAs. If DSBs are incurred after the S-phase and are improperly repaired, CSAs  will result (Danford, 2012; Registre et al., 2016; Vodicka et al., 2018). Similarly, CNVs are thought to be induced during the DNA replication phase. DNA replication stops can also be problematic for repair. Although the mechanism is not well studied, it has been suggested that stress during replication, in particular stalling replication forks, prompt microhomology-mediated mechanisms to overcome the replication stall, which often results in duplications or deletions. Two models that have been proposed to explain this mechanism include the Fork Stalling and Template Switching (FoSTeS) model, and the Microhomology-Mediated Break-Induced Replication (MMBIR) model (Lee et al. 2007; Hastings et al. 2009; Arlt et al. 2012; Arlt et al. 2014; Wilson et al. 2015).

The type of CA may also be dependent on the type of erroneous repair that occurs. Deletions or chromosome breaks may occur when DSBs are left unrepaired (Danford 2012). Deletions may also occur when nucleotides are removed at the junctions (Schipler and Iliakis 2013) or when the wrong DNA ends are religated (Venkitaraman 2002). Ligation of the incorrect ends of DNA DSBs may also lead to translocations or dicentrics (Ferguson & Alt, 2001;  Lieber, 2010; Povirk, 2006; Venkitaraman, 2002). This type of error may occur when there are two or more DSBs in close proximity to each other that are misrejoined, thus resulting in the exchange of genetic material between two chromosomes (Ferguson and Alt 2001; Povirk 2006). NHEJ has been shown to play a significant role in the generation of chromosomal exchanges ( Lieber 2010; Povirk 2006; Weinstock et al. 2006). Evidence for this comes from analysis of breakpoint junctions, which typically have little to no chromosomal homology when NHEJ repair is used (Povirk 2006; Weinstock et al. 2006); this was demonstrated in studies using translocation reporters (reviewed in Weinstock et al., 2006). There are, however, two types of NHEJ. c-NHEJ has been shown to suppress exchanges (Simsek and Jasin 2010) , which may be due to its relatively rapid repair kinetics (Schipler and Iliakis 2013). Chromosomal exchanges are thus suggested to originate more often from alt-NHEJ (Simsek and Jasin 2010; Zhang and Jasin 2011; Schipler and Iliakis 2013) .

NHEJ is also thought to mediate the formation of other types of CAs. Based on analysis of breakpoint junctions in lung adenocarcinoma samples where reciprocal inversions were found between genes RET and KIF5B/CCDC6, the majority of the inversions were thought to be induced by NHEJ (Mizukami et al. 2014). Chromothripsis, which refers to a single event that results in a massive number of CAs localized to a single or very few chromosomes (Russo et al. 2015; Leibowitz et al. 2015; Rode et al. 2016), may also be linked to NHEJ. The single catastrophic event sparking chromothripsis likely induces a large quantity of DSBs, essentially shattering the chromosome(s). These DSBs are then processed mainly by the error-prone NHEJ, which results in a large number of CAs, including chromosomal rearrangements, CNVs, and loss of heterozygosity (Leibowitz et al. 2015; Rode et al. 2016).

Fusing two broken chromosomes may lead to the formation of dicentric chromosomes, which are characterized by the presence of two centromeres. Dicentrics may also be formed by telomere-to-telomere end fusions (Fenech and Natarajan 2011; Rode et al. 2016). Telomeres, composed of TTAGGG repeats, are important structures that protect the ends of chromosomes and ensure accurate replication (Ferguson and Alt 2001; Hoeijmakers 2001; Vodicka et al. 2018); these nucleoprotein structures are shortened (Vodicka et al. 2018) by approximately 100 base pairs after each division, and are only replenished in cell types expressing the enzyme telomerase (Hoeijmakers 2001). If the telomeres become critically short, they can be mistaken for broken DNA ends by DNA repair machinery, and thus may be ‘repaired’ by fusing the ends of two chromosomes together (Ferguson and Alt 2001; Vodicka et al. 2018). 

Dicentrics can also contribute to other types of CAs. During mitosis, the two centromeres of a dicentric chromosome may be pulled to opposite ends of the cell by mitotic spindle (Ferguson and Alt 2001; Fenech and Natarajan 2011; Leibowitz et al. 2015; Rode et al. 2016). Because the ends of the chromosomes are fused, this can lead to the formation of an anaphase chromatin bridge between the daughter cells (Russo et al. 2015; Leibowitz et al. 2015; Rode et al. 2016). If this bridge persists beyond anaphase, it may become enclosed in a nucleoplasmic membrane along with the nucleus, thus generating a NPB (Fenech and Natarajan 2011). Eventually, however, these bridges do break (Ferguson and Alt 2001; Fenech and Natarajan 2011; Russo et al. 2015; Leibowitz et al. 2015; Rode et al. 2016); the break is nearly always uneven, meaning that one daughter cell will be missing genetic material and one will have extra genetic material (Fenech and Natarajan 2011). These fragments, with their ‘sticky’ ends from the break, may further propagate the formation of CAs by being ligated inappropriately to another chromosome. Thus the cycle, known as the breakage-fusion-bridge (BFB) cycle, is propagated and further contributes to chromosomal instability (Ferguson and Alt 2001; Fenech and Natarajan 2011; Russo et al. 2015; Leibowitz et al. 2015; Rode et al. 2016) . 

MN may also be formed during this BFB cycle. When the anaphase bridges break, the remaining chromosome fragments may be packaged by a nuclear membrane into its own mini nucleus, thus, forming an MN. MN may also enclose acentric chromosome fragments, chromatid fragments, or even entire chromosomes that were not properly segregated during mitosis (Fenech and Natarajan 2011; Doherty et al. 2016). Similar to MN in structure are NBUDs; the only difference between these two structures is that NBUDs are still attached to the nucleus by nucleoplasmic material. A NBUD is formed if there is amplified DNA that needs to be removed; this amplified material is often segregated from the other DNA at the periphery of the nuclear membrane and excluded from the nucleus by budding, resulting in a NBUD. Additionally, NBUDs may also result from NPB breakages (Fenech and Natarajan 2011).

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 in this KER are as follows:

  1. In an experiment using both wild-type and Ku70-/- cells, knock-down of alt-NHEJ protein CtIP resulted in significantly decreased translocations in both cell types. When CtIP expression was rescued, translocation frequencies in these cells also returned to normal levels. This however, is opposite to results obtained in a similar study, where knock-out of Ku70 or Xrcc4 led to increased translocation frequency, and Xrcc4 rescue experiments resulted in decreased translocations (Simsek and Jasin 2010). It should be noted that alt-NHEJ is thought to be the major repair pathway responsible for generating translocations (Simsek and Jasin 2010; Zhang and Jasin 2011; Schipler and Iliakis 2013).  
  2. There is currently discussion regarding the accuracy of HR relative to NHEJ. Traditionally HR has been considered the more accurate type of DNA repair, while NHEJ is classically described as error-prone. There is emerging evidence, however, suggesting that HR may in fact be a mutagenic process. Evidence supporting HR as an error-prone repair pathway has been reviewed (Guirouilh-barbat et al. 2014).

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

DNA repair is a modulating factor in this KER. The progression from “Inadequate DNA repair” to “Increase, Chromosomal aberrations” only occurs when "Increase, DNA strand breaks" (KE 1635) precedes "Inadequate DNA repair", which indicates that DNA strand breaks could not be repaired.   

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Studies directly examining the response-response relationship between inadequate repair and CA frequency are lacking. One study examined both DNA repair and CA frequency in cells exposed to DNA-PK inhibitor wortmannin. There was a negative, approximately linear relationship between DNA repair and increasing wortmannin dose, and a positive, approximately linear relationship between MN frequency and increasing wortmannin dose; this suggests that as adequate DNA repair declines, CA frequency increases (Chernikova et al. 1999). More studies are required, however, that directly quantify the response-response relationship between inadequate DNA repair and CAs. 

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

The time scale between inadequate DNA repair and the increased frequency of CAs has not been well-established. Most data come from studies that assess only one of these events in relation to a radiation stressor rather than assessing the timing of the events relative to each other. More studies are thus required that directly assess this relationship.

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 chromosomes. The majority of the evidence is from in vitro fetal human male models. No in vivo evidence was found to support the relationship. 


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

Arlt, M.F. et al. (2014), "NIH Public Access", 55(2):103–113. doi:10.1002/em.21840.

Arlt, M.F., T.E. Wilson & T.W. Glover (2012), "Replication Stress and Mechanisms of CNV Formation.", Curr. Opin. Genet. Dev. 22(3):204–210. doi:10.1016/j.gde.2012.01.009.

Balajee, A.S. (2014), "Multicolour FISH analysis of ionising radiation induced micronucleus formation in human lymphocytes.", Mutagenesis, 29(6):447–455. doi:10.1093/mutage/geu041.

Bignold, L.P. (2009), "Mechanisms of clastogen-induced chromosomal aberrations : A critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes.", Mutat. Res. 681:271–298. doi:10.1016/j.mrrev.2008.11.004.

Bonassi, S. (2008), "Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22 358 subjects in 11 countries.", Carninogenesis, 29(6):1178–1183. doi:10.1093/carcin/bgn075.

Bucher, M. et al., (2021), Analysis of chromosomal aberrations and γH2A.X foci to identify radiation-sensitive ataxia-telangiectasia patients., Mutat Res., Jan-Feb;861-862

Chernikova, S.B., R.L. Wells & M.M. Elkind (1999), "Wortmannin Sensitizes Mammalian Cells to Radiation by Inhibiting the DNA-Dependent Protein Kinase-Mediated Rejoining of Double-Strand Breaks.", Radit. Res. 151(2):159–166. doi: 10.2307/3579766.

Cornforth, M. & J. Bedford (1985), "On the Nature of a Defect in Cells from Individuals with Ataxia-Telangiectasia.", Science 227(4694):1589–1591. doi:10.1126/science.3975628.

Danford, N. (2012), "The Interpretation and Analysis of Cytogenetic Data.", Methods Mol. Biol. 817:93-120, doi:10.1007/978-1-61779-421-6.

Doherty, A., S.M. Bryce & J.C. Bemis (2016), "The In Vitro Micronucleus Assay.", Elsevier Inc.

Durante, M. and F. Cucinotta. (2008), “Heavy ion carcinogenesis and human space exploration”, Nature Reviews Cancer, Vol.8/6, Nature Portfolio, Berlin,

Fenech, M. & A.T. Natarajan (2011), "Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. 26(1):125–132. doi:10.1093/mutage/geq052.

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.

Foray, N., M. Bourguignon and N. Hamada. (2016), “Individual response to ionizing radiation”, Mutation Research - Reviews in Mutation Research, Vol.770, Elsevier, Amsterdam,  

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.

George, K.A. et al. (2009), "Dose Response of γ Rays and Iron Nuclei for Induction of Chromosomal Aberrations in Normal and Repair-Deficient Cell Lines Dose Response of c Rays and Iron Nuclei for Induction of Chromosomal Aberrations in Normal and Repair-Deficient Cell Lines." Radit. Res., 171(6):752–763. doi:10.1667/RR1680.1.

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

Hagmar, L. et al. (2004), "Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk: Results from Nordic and Italian Cohorts.", Cancer Res. 64(6):2258–2263. doi: 10.1158/0008-5472.CAN-03-3360.

Han, J., Ruan, C., Huen, M.S.Y. et al. (2017) “BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability”. Nat Commun 8, 1470   

Hastings, P.J., G. Ira & J.R. Lupski (2009), "A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation.", 5(1). doi:10.1371/journal.pgen.1000327.

Heterodimer, K. et al. (2002), "Myeloid Leukemias Have Increased Activity of the Nonhomologous End-Joining Pathway and Concomitant DNA Misrepair that Is Dependent on the Ku70/86 Heterodimer.", Cancer Res. 62(10):2791-7.

Hunter, N. & C.R. Muirhead (2009), "Review of relative biological effectiveness dependence on linear energy transfer for low-LET radiations Review of relative biological effectiveness dependence.", J. Radiol. Prot. doi:10.1088/0952-4746/29/1/R01.

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.

Karanjawala, Z.E. et al. (1999), "The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts.", Curr. Biol. 9(24):1501-4. doi: 10.1016/S0960-9822(00)80123-2.

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

Lee, J.A., C.M.B. Carvalho & J.R. Lupski (2007), "A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders.", Cell. 131(7):1235–1247. doi:10.1016/j.cell.2007.11.037.

Leibowitz, M.L., C. Zhang & D. Pellman (2015), "Chromothripsis: A New Mechanism for Rapid Karyotype Evolution.", Annu. Rev. Genet. 49:183-211, doi:10.1146/annurev-genet-120213-092228.

Lieber, M.R. et al. (2010), "Nonhomologous DNA End Joining (NHEJ) and Chromosomal Translocations in Humans.", Subcell. Biochem., 50:279-96  doi:10.1007/978-90-481-3471-7.

Lin, Y. et al. (2014), "Differential Radiosensitivity Phenotypes of DNA-PKcs Mutations Affecting NHEJ and HRR Systems following Irradiation with Gamma-Rays or Very Low Fluences of Alpha Particles.", PLoS One. 9(4):2–11. doi:10.1371/journal.pone.0093579.

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.

Manova, V. & D. Gruszka (2015), "DNA damage and repair in plants - from models to crops.", Front Plant Sci. 6(October):885. doi:10.3389/fpls.2015.00885.

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.

Mizukami, T. et al. (2014), "Molecular Mechanisms Underlying Oncogenic RET Fusion in lung adenocarcinoma", J. Thorac. Oncol. 9(5):622–630. doi:10.1097/JTO.0000000000000135.

Patel, K.J. et al. (1998), "Involvement of Brca2 in DNA Repair.", Mol. Cell. 1(3):347-57. doi: 10.1016/S1097-2765(00)80035-0.

Pfeiffer, P. & W. Goedecke (2000), "Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations.", Mutagenesis 15(4):289-302. doi:

Povirk, L.F. (2006), "Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks.", DNA Repair (Amst.) 5(9-10):1199–1212. doi:10.1016/j.dnarep.2006.05.016.

Proietti De Santis, L., C. L. Garcia, A. S. Balajee, G. T. Brea Calvo, L. Bassi, & F. Palitti (2001), "Transcription coupled repair deficiency results in increased chromosomal aberrations and apoptotic death in the UV61 cell line, the Chinese hamster homologue of Cockayne's syndrome B", Mutat Res, 485(2): 121–132.

Qian, Q. et al. (2016), "Effects of Ionising Radiation on Micronucleus Formation and Chromosomal Aberrations in Chinese.", Radiat. Prot. Dosimetry 168(2):‌197–203. doi: 10.1093/rpd/ncv290

Registre, M., R. Proudlock & N. Carolina (2016), "The In Vitro Chromosome Aberration Test.", Elsevier Inc. Genetic Toxicology Testing, pp.207-267. doi: 10.1016/B978-0-12-800764-8.00007-0.

Rode, A. et al. (2016), "Chromothripsis in cancer cells: An update.", Int. J. Cancer, 2333:2322–2333. doi:10.1002/ijc.29888.

Russo, A. et al. (2015), "Review Article Genomic Instability: Crossing Pathways at the Origin of Structural and Numerical Chromosome Changes.", Envrion. Mol. Mutagen. 56(7):563-580. doi:10.1002/em.

Schipler, A. & G. Iliakis (2013), "DNA double-strand – break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.", Nucleic Acids Res., 41(16):7589–7605. doi:10.1093/nar/gkt556.

Simsek, D. & M. Jasin (2010), "Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4/ligase IV during chromosomal translocation formation", Nat. Struct. Mol. Bio. 17(4):410–416. doi:10.1038/nsmb.1773.

Sishc, B.J. & A.J. Davis (2017), "The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer.", Cancers (Basel), 9(7) pii E81, doi:10.3390/cancers9070081.

Suto, Y. et al. (2015), "Construction of a cytogenetic dose – response curve for low-dose range gamma-irradiation in human peripheral blood lymphocytes using three-color FISH", Mut. Res. / Gen. Tox. and Environ. Mut. 794:32–38.

Thomas, P., K. Umegaki & M. Fenech (2003), "Nucleoplasmic bridges are a sensitive measure of chromosome rearrangement in the cytokinesis-block micronucleus assay.", Mutagenesis, 18(2):187-194, doi:10.1093/mutage/18.2.187.

Tucker, J.D. et al. (2005), "Persistence of Chromosome Aberrations Following Acute Radiation: I, PAINT Translocations, Dicentrics, Rings, Fragments, and Insertions.", Environ. Mol. Mutagen, 45(2-3):229-249. doi:10.1002/em.20090.

Varga, T. & P.D. Aplan (2005), "Chromosomal aberrations induced by double strand DNA breaks.", DNA Repair (Amst). 4(9):1038–1046. doi:10.1016/j.dnarep.2005.05.004.

Venkitaraman, A.R. (2002). "Cancer susceptibility and the Functions of BRCA1 and BRCA2.", Cell 108(2):171–182.

Vodicka, P. et al. (2018), "Genetic variation of acquired structural chromosomal aberrations.", Mutat. Res. Gen. Tox. En. 836(May):13–21. doi:10.1016/j.mrgentox.2018.05.014.

Weinstock, D.M. et al. (2006), "Modeling oncogenic translocations: Distinct roles for double-strand break repair pathways in translocation formation in mammalian cells.", DNA Repair (Amst.) 5(9-10):1065–1074. doi:10.1016/j.dnarep.2006.05.028.

White, J. S., S. Choi, & C. J. Bakkenist (2010), "Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange", Sci Signal, 3(124): ra44.

Wilhelm, T. et al. (2014), "Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells.", Proc. Natl. Acad. Sci. 111(2):763-768. doi:10.1073/pnas.1311520111.

Wilson, J.W. et al. (2015), "The effects of extremely low frequency magnetic fields on mutation induction in mice.", Mutat Res - Fundam Mol Mech Mutagen. 773:22–26. doi:10.1016/j.mrfmmm.2015.01.014.

Zhang, Y. & M. Jasin (2011), "An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway.", Nat Publ Gr. 18(1):80–84. doi:10.1038/nsmb.1940.

Zhi, Y., H. Ji, J. Pan, P. He, X. Zhou, H. Zhang, Z. Zhou, & Z. Chen (2017), "Downregulated XPA promotes carcinogenesis of bladder cancer via impairment of DNA repair", Tumour Biol, 39(2): 1010428317691679.