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Increase, DNA strand breaks leads to Inadequate DNA repair
Key Event Relationship Overview
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||Carole Yauk (send email)||Open for comment. Do not cite||WPHA/WNT Endorsed|
|Deposition of energy leading to lung cancer||adjacent||Moderate||Moderate||Vinita Chauhan (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Deposition of energy leading to occurrence of cataracts||adjacent||Moderate||Moderate||Vinita Chauhan (send email)||Open for citation & comment|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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). HR is mostly operative during S and G2 phases because of the presence of the sister chromatid that can be used as template for 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. 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. 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
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
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 (van Gent et al., 2001; Khanna & Jackson, 2001; Vignard et al., 2013; Moore et al., 2014; Rothkamm et al., 2015; Chang et al., 2017; Lobrich 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).
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
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
Effects on the KER
Linear energy transfer (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
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).
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
Domain of Applicability
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.
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