Upstream eventN/A, Inadequate DNA repair
Increase, Chromosomal aberrations
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Oxidative DNA damage leading to chromosomal aberrations and mutations||adjacent||High||Low|
|Direct deposition of ionizing energy leading to lung cancer||adjacent||High||Low|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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 a 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 a 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 religate 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).
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). 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 (CTAs) that affect both sister chromatids, and chromatid-type aberrations (CSAs), affecting only one chromatid (Danford, 2012) . Examples of CTAs include chromosome-type breaks, centric ring chromosomes, and dicentric chromosomes (which have two centromeres), while CSAs 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 Supporting this KER
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 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). 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 centred 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. 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 (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 and a translocated chromosome (Ferguson and Alt 2001; Povirk 2006). NHEJ has been shown to play a significant role in the generation of translocations ( 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 translocations (Simsek and Jasin 2010) , which may be due to its relatively rapid repair kinetics (Schipler and Iliakis 2013). Translocations 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, dicentric chromosomes 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).
There is moderate empirical evidence supporting the relationship between inadequate DNA repair and the frequency of CAs. The evidence presented below is summarized in table 6, here (click link). Several reviews discuss evidence that associates these two events (Ferguson and Alt 2001; van Gent et al. 2001; Sishc and Davis 2017; Venkitaraman 2002). Overall, however, there is weak empirical evidence available supporting a dose and incidence concordance, little empirical evidence supporting a temporal concordance, and strong empirical evidence supporting essentiality for this KER.
Dose and Incidence Concordance
There is weak empirical evidence available that directly examines the dose and incidence concordance between DNA repair and CAs within the same study. There are, however, studies that use an ionizing radiation stressor to examine dose concordance of either inadequate DNA repair in response to radiation exposure, or CA frequencies in response to irradiation. In an analysis that amalgamated results from several different studies conducted using in vitro experiments, the rate of DSB misrepair was revealed to increase in a dose-dependent fashion from 0 - 80 Gy (Mcmahon et al. 2016). Similarly, there was a clear correlation between radiation dose (i.e., increasing amounts of energy deposition) between 0 - 10 Gy and different clastogenic endpoints (Thomas et al. 2003; Tucker et al. 2005A; George et al. 2009; Arlt et al. 2014; Balajee et al. 2014; Lin et al. 2014; Suto et al. 2015; Mcmahon et al. 2016) . Overall, this suggests that exposure to radiation may increase both inadequate repair of DNA damage and the frequency of CAs in a dose-dependent fashion. More studies, however, are required to better assess the dose and incidence concordance of this KER.
Temporal concordance between inadequate DNA repair and CA frequency is not well established. One study using cells pretreated with a DNA-PK inhibitor and irradiated with gamma rays found that DNA repair and MN were evident when they were assessed at 3 hours post-irradiation and 24 hours post-irradiation, respectively (Chernikova et al. 1999). This study does therefore suggest that there may be temporal concordance between these two events. Other radiation-based studies examining these two events separately, however, do not provide clear evidence of temporal concordance between DNA repair and CA frequency.
There is strong evidence for essentiality. Numerous studies demonstrate that simply knocking-out one gene involved in DNA repair, without any other added stressor, is enough to increase the frequency of CAs in several types of cells (Karanjawala et al. 1999; Patel et al. 1998; Wilhelm et al. 2014). Further fortifying this relationship, addition of a DSB-inducing stressor to these DNA repair knock-out cells also significantly increases CA levels relative to wild-type cells receiving the same treatment (Cornforth and Bedford 1985; Simsek and Jasin 2010; Lin et al. 2014; Mcmahon et al. 2016) .
Inhibitor studies have also found similar results. Two strains of wild-type cells that were treated with hydroxyurea, which is known to inhibit DNA repair, both had increased CAs relative to untreated wild-type cells (Wilhelm et al. 2014). Similarly, immortalized myeloid cell lines, cells from patients with myeloid leukemia, and cells from healthy donors were all found to have dose-dependent decreases in ligation efficiency after being treated with increasing doses of antibodies against various NHEJ proteins (Heterodimer et al. 2002). Lastly, cells that were pretreated with DNA-PK inhibitor wortmannin prior to being irradiated were found to have not only increased levels of MN, but also decreased rates of DNA rejoining (Chernikova et al. 1999).
A rescue experiment provided further evidence of the essential role DNA repair plays in relation to CA frequencies. Inhibition of NHEJ through knocking out either Ku70 or Xrcc4 resulted in higher CA frequencies in the form of translocations; when Xrcc4 was transiently expressed in Xrcc4-/- cells, translocations were significantly decreased by 5-fold(Simsek and Jasin 2010) . This provides strong evidence that the NHEJ repair pathway plays an important role in the formation of CAs, specifically translocations.
Uncertainties and Inconsistencies
Uncertainties in this KER are as follows:
- 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).
- 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).
Quantitative Understanding of the Linkage
Quantitative understanding of this linkage is lacking. Most data is derived from the studies that examined DSB misrepair rates or CA rates in response to a radiation stressor. In terms of inadequate DNA repair, the rate of DSB misrepair was found to be approximately 10 - 15% at 10 Gy of radiation (Lobrich et al. 2000); this rate increased to 50 - 60% at a radiation exposure of 80 Gy (Kuhne et al. 2000; Lobrich et al. 2000; Mcmahon et al. 2016). It is not known, however, how this rate of inadequate repair directly relates to CA frequency. Overall, more studies are required that directly assess this relationship.
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 assess the quantitative response-response relationship between inadequate DNA repair and CAs.
The time scale between inadequate DNA repair and the increased frequency of CAs has not been well-established. Most data comes 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 modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability for this KER is multicellular eukaryotes at any stage of development, including plants (Varga & Aplan 2005; Schipler & Iliakis 2013; Manova & Gruszka 2015).
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