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Relationship: 2608

Title

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

Increased, DNA damage and mutation leads to Inadequate DNA repair

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, DNA damage and mutation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Inadequate DNA repair

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
DNA damage and mutations leading to Metastatic Breast Cancer	adjacent	High	High	Usha Adiga (send email)	Under development: Not open for comment. Do not cite	Under Development

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	High	NCBI
mouse	Mus musculus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Not Otherwise Specified	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

Upstream event: Increased, DNA damage and mutation

Downstream event: DNA repair mechanism, Reduced

The Key Event Relationship (KER) described involves a cascade of events related to DNA integrity and repair. The upstream event entails "Increased DNA damage and mutation," wherein exposure to various genotoxic agents leads to the accumulation of DNA lesions and mutations. These genetic alterations can arise from factors like chemical exposure, radiation, or other external agents.

The downstream event in this KER is the "Reduced DNA repair mechanism." As a response to increased DNA damage and mutations, the cellular machinery responsible for DNA repair mechanisms becomes compromised or less effective. The cell's ability to identify and rectify DNA lesions and mutations is hindered, potentially due to the overwhelming load of damage or the inefficiency of repair pathways.

Together, this KER illustrates a cause-and-effect relationship wherein heightened DNA damage and mutations contribute to a reduction in the cell's DNA repair mechanisms. This sequence of events highlights the delicate balance between damage induction and repair processes within the cell, emphasizing the importance of understanding these interactions for maintaining genomic stability and preventing the accumulation of detrimental mutations.

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

In accordance with OECD guidelines, the evidence collection strategy for the Key Event Relationship (KER) "Increased DNA damage and mutation leads to Inadequate DNA repair" was meticulously designed and executed. To establish increased DNA damage and mutation as the initial event, a battery of well-recognized genotoxicity assays was employed, including the Ames test and in vitro micronucleus assay, providing direct evidence of genotoxic agent-induced genetic harm. Complementing this, a comprehensive assessment of DNA repair mechanisms was carried out using comet assays and gene expression analysis of DNA repair genes, concretely demonstrating the occurrence of inadequate repair. Strengthening the KER's mechanistic plausibility, mechanistic studies delved into the intricate connections between DNA damage, mutation, and DNA repair insufficiency. Real-world relevance was fortified by integrating epidemiological studies that established a significant correlation between exposure to genotoxic agents and escalated mutagenesis, concurrently pointing towards DNA repair deficiency in exposed human populations. This meticulously constructed evidence base, in accordance with OECD principles, affirms the robustness and reliability of the "Increased DNA damage and mutation leads to Inadequate DNA repair" KER.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

DNA damage leading to inadequate repair mechanisms :

As a result of DNA damage, DNA repair activities change. A variety of genotoxic agents, such as N-nitrosodimethylamine, aflatoxin B1, and 2-acetylaminofluorene induce the protein, O6-Alkylguanine-DNA alkyltransferase (ATase), which is responsible for repair of DNA alkylation damage in rats (O’Connor, 1989; Chinnasamy et al.,1996). Grombacher and Kaina (1996) reported an increased human ATase mRNA expression by alkylating agents like N-methyl-N′-nitro-N-nitrosoguanidine and methyl methanesulphonate and by ionizing radiation via the induction of the ATase promoter. ATase mRNA expression was increased in response to treatment with 2-acetylaminofluorene in rat liver (Potter et al., 1991; Chinnasamy et al., 1996). In another study, it was demonstrated that ATase gene induction is p53 gene-dependent: ATase activity was induced in mouse tissues following γ-irradiation in p53 wild type mice, but not in p53 null animals (Rafferty et al., 1996).
Alkylating agents and X-rays also induce DNA glycosylase, alkylpurine-DNA-N-glycosylase (APNG) (Lefebvre et al., 1993; Mitra and Kaina, 1993).
As a consequence of these and other observations, there is considerable interest in investigating DNA repair modulation as a possible risk factor in carcinogenesis.

Due to low levels of reactive oxygen species (ROS) and other free radicals generated by endogenous redox reactions, oxidative DNA lesions are present in the cell at steady state.
The most important oxidative DNA lesions include 7, 8-dihydro-8oxo-deoxyGuanine (8-oxo-dG), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FaPydG), and thymidine glycol (Tg).
Under homeostatic settings, cells can control the amount of free radicals in the environment and quickly repair oxidised DNA bases with basal repair mechanisms, preventing irreparable damage (Swenberg et al., 2011). Oxidative DNA lesions are mainly repaired by base excision repair (BER) initiated by DNA glycosylases such as oxoguanine glycosylase 1 (OGG1), endonuclease III homologue 1 (NTH1), and Nei-like DNA glycosylases (NEIL 1/2), which detect and remove damaged bases.
Endonucleases or lyases cleave abasic sites, resulting in transitory single-strand breaks (SSB) that can be repaired in either short-patch or long-patch fashion. To a lesser extent, nucleotide excision repair (NER) is involved in repairing oxidised bases. (Shafirovich et al., 2016).
Increased levels of free radicals or exposure to oxidising agents can increase the number of oxidative DNA lesions and overload repair mechanisms, lowering repair quality. If the repair mechanisms are weakened, oxidative lesions might build up (insufficient repair), resulting in erroneous base pairing during replication or incomplete repair (indicated by accumulation of repair intermediates) (Markkanen et al., 2017).

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

BER and, to a lesser extent, NER are used to repair oxidative DNA damage. Previous research has found thresholded dose-response curves in oxidative DNA damage and attributed these findings to a lack of repair capability at the curve's inflection point (Gagne et al., 2012; Seager et al., 2012). Following chemical exposures, in vivo, a rise and buildup of oxidative DNA lesions was seen despite the activation of BER, suggesting poor repair of oxidative DNA lesions beyond a certain level(Ma et al., 2008).

OGG1 and NTH1, the glycosylases that initiate the BER of 8-oxo-dG and thymine glycol (Tg) lesions, respectively, are bifunctional, containing both glycosylase and lyase activities. By cleaving the glycosidic link, the glycosylase eliminates the oxidised guanine and creates an apurinic site.The lyase then cleaves the phosphodiester bond 5’ to the AP site; a transient SSB is created for further processing in BER (Delaney et al., 2012). Abasic sites created by OGG1 and other glycosylases are also processed by apuric/apyrimidinic endonucleases (APE1) to create the 5’ nick (Allgayer et al., 2016).

Previous research has shown that an imbalance in any of the BER's several phases might result in an accumulation of repair intermediates and failed repair. Given that OGG1 is slower than other glycosylases in releasing its catalytic product, a disproportionate rise in oxidative DNA lesions compared to the quantity of accessible OGG1 is highly likely to result in an imbalance between lesions and the BER initiating step (Brenerman et al., 2014). As a result, oxidative lesions would begin to accumulate. Furthermore, overexpression of OGG1 and NTH1 has been linked to the accumulation of SSB, suggesting that the unbalanced lyase activity causes an excess of SSB intermediates(Yang et al., 2004; Yoshikawa et al., 2015; Wang et al., 2018).

Increases in oxidative lesions may result in more lesions and repair intermediates being produced in close proximity. Previous research on mammalian cell extracts has shown that when oxidative damages occur in parallel or opposite each other, repair effectiveness is reduced.OGG1 showed reduced binding to 8-oxo-dG near an AP site incision. Furthermore, the OGG1-8-oxo-dG complex has been observed to hinder the repair of neighbouring AP site incision, delaying the completion of BER; It's been claimed that this interaction between BER enzymes causes a buildup of oxidative lesions and repair intermediates(Pearson et al., 2004; Budworth et al., 2005; Bellon et al., 2009; Yoshikawa et al., 2015; Sharma et al., 2016).

If oxidative lesions persist in the genome due to insufficient repair, incorrect base insertion opposite unrepaired oxidative DNA lesions may occur during replication. This is a well-established event. For example, 8-oxo-dG and FaPydG, the two most prominent oxidative DNA lesions, are able to form base pairs with dATP, giving rise to G:C→T:A transversions after subsequent DNA synthesis (Freudenthal et al., 2013; Gehrke et al., 2013; Markkanen, 2017). Replicative DNA polymerases such as DNA polymerase α, δ, and ε (pol α, δ, ε) have a poor ability to extend the DNA strand past 8-oxo-dG:dCTP base pairs and may cause replication to stall or incorrectly insert dATP opposite 8-oxo-dG (Hashimoto et al., 2004; Markkanen et al., 2012). In stalled replication forks, repair polymerases may be recruited to perform translesion DNA synthesis (TLS). Human Y-family DNA polymerases (Rev 1, pol κ, ι, and η) are DNA repair polymerases mainly involved in TLS in stalled replication forks. However, TLS is not free of error and its accuracy differs for each repair polymerase. For example, it is known that pol κ and η perform TLS across 8-oxo-dG and preferentially insert dATP opposite the lesion, generating G:C→T:A transversions. The error-prone nature of bypassing unrepaired oxidative lesions has been described in many previous studies and reviews (Greenberg, 2012; Maddukuri et al., 2014; Taggart et al., 2014; Shah et al., 2018).

Repair by OGG1 requires 8-oxo-dG:dC base pairing, thus, it is unable to repair 8-oxo-dG:dA mispairing in newly synthesized strands. The repair of 8-oxo-dG:dA base pairs post-replication is performed by MUT Y homologue, MYH, an adenine DNA glycosylase. However, the removal of dA instead of the damaged guanine may lead to futile cycles of BER because: 1) another dA is often inserted opposite the lesion, or 2) BER ligases have a poor ability of ligating the 3’end of dC opposite 8-oxo-dG (Hashimoto et al., 2004; Caglayan and Wilson, 2015). Accumulated 8-oxo-dG may be more resistant to repair post-replication due to this futile BER.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In vitro studies demonstrating dose and temporal concordance, or essentiality

- Human normal hepatocytes (HL-7702) were subjected to escalating doses of N,N-dimethylformamide for 24 hours (C. Wang et al., 2016)
- At all concentrations, a concentration-dependent increase in ROS was detected; the rise was statistically significant when compared to control (6.4, 16, 40, 100 mM)
- Until the highest two concentrations (40 and 100 mM), no significant rise in 8-oxodG was seen, indicating inadequate repair at these dosages.
- Excision repair genes (XRCC2 and XRCC3) were considerably up-regulated at 6.4 and 16 mM, well below the doses that significantly produced 8-oxodG, indicating that adequate DNA repair was possible at these low concentrations.
- These findings show that repair is competent at low concentrations (removing 8-oxodG quickly), but that repair is swamped (i.e., insufficient) at larger doses, where 8-oxodG greatly increases.
AS52 Chinese hamster ovary cells (wild type and OGG1-overexpressing) were exposed to varying doses of ultraviolet A (UVA) radiation (Dahle et al., 2008)
- Formamidopyrimidine glycosylase (Fpg)-sensitive sites were quantified using alkaline elution after increasing repair times (0, 1, 2, 3, 4 h) following 100 kJ/m² UVA irradiation
- OGG1-overexpressing AS52 cells (OGG1+): Fpg-sensitive sites reduced to 71% within half an hour and down to background levels at 4h
- Wild type AS52 cells: at 4h, 70% of the Fpg-sensitive sites remained, indicating accumulation of oxidative lesions
- Mutations in the Gpt gene was quantified in both wild type and OGG1+ cells by sequencing after 13-15 days following 400 kJ/m²UVA irradiation
  - G:C→T:A mutations in UVA-irradiated OGG1+ cells were completely eliminated (thus, repair was sufficient when repair overexpressed).
  - G:C→T:A mutation frequency in wild type cells increased from 1.8 mutants/million cells to 3.8 mutants/million cells following irradiation – indicating incorrect repair or lack of repair of accumulated 8-oxo-dG.
  - The importance of 8-oxo-dG production in oxidative DNA damage-induced G to T transversion mutations is further demonstrated by the above result.

HL-60 human leukemia cells were irradiated with X-rays at a rate of 0.5 Gy/min for increasing durations (i.e., increasing doses). 8-OHdG levels were quantified by HPLC as number of 8-OHdG per 10⁶ deoxyguanosine (Li et al., 2013)
- No increase in 8-OHdG was observed up to 2 Gy (sufficient repair at low doses), above which the level of lesions increased linearly up to 20 Gy (insufficient repair)
- In the same study described below, a thresholded dose-response curve, indicating of overwhelmed repair processes, was also seen in mouse liver.

In vivo studies demonstrating dose concordance

Two groups of 5-week-old C57BL/6J mice were exposed to increasing doses of X-rays at a rate of 0.5 Gy/min (200 kV, 12 mA). The livers of one group of mice were obtained immediately after exposure, while urine samples were collected over the course of 24 hours after irradiation in the second group of mice(Li et al., 2013).
- The amount of 8-OHdG in mouse liver DNA was measured by HPLC and expressed as 8-OHdG per 10⁶ deoxyguanosine
- Between 0 and 0.5 Gy, no increase in lesions was observed
- Between 0.5 and 30 Gy, a linear dose-response in 8-OHdG was observed
- The thresholded dose-response curve was concordant in the urine samples; no increase in urinary 8-OHdG (8-OHdG/creatinine (ng/mg)) was observed between 0 and 0.1 Gy but between 0.1 and 5 Gy, the number of lesions increased linearly with dose

For 30 days, male Sprague-Dawley rats were fed 0.5 mmol aniline/kg/day. Spleen tissues were used to acquire genomic DNA, nuclear extracts, and mitochondrial extracts (Ma et al., 2008).
- 8-OHdG was measured on digested genomic DNA using an enzyme-linked immunosorbent assay (ELISA). The number of lesions in aniline-fed rats was 2.8 times higher than in control rats.
- OGG1 activity was measured in both nuclear and mitochondrial extracts of aniline-treated rats, with a 1.32-fold and 1.15-fold increase in enzyme activity (both significant; p0.05) seen in the corresponding extracts.
- Western blotting was used to assess the OGG1 enzyme content in the extracts; the increase in OGG1 content in aniline-treated rats was consistent with the OGG1 activity assay.
- The amount of 8-OHdG rose despite an increase in OGG1 enzyme concentration and activity.

- These findings show that because 8-oxodG adducts are rapidly eliminated, repair is sufficient at low doses. 8-oxo-dG begins to significantly increase at larger concentrations, indicating that repair is being overwhelmed (i.e., insufficient).

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

Despite the fact that OGG1's dual activity as a glycosylase and lyase has been widely acknowledged and proved experimentally, investigations suggest that apurinic endonuclease 1 is primarily responsible for the cleavage of phosphodiester link 5' to the lesion (APE1) (Allgayer et al., 2016; R. Wang et al., 2018). In rare circumstances, APE1 may be the primary driver of BER intermediate buildup. According to some research, OGG1 is involved in the repair of non-transcribed strands but isn't essential for transcription-coupled 8-oxo-dG repair.; Le Page et al. reported efficient repair of 8-oxo-dG in the transcribed sequence in Ogg1 knockout mouse cells (Le Page et al., 2000). Furthermore, the repair of 8-oxo-dG is influenced by the sequences surrounding it; the location of the lesions may have a negative impact on repair effectiveness. (Pastoriza-Gallego et al., 2007). We note that the study by Allgayer et al. was investigating the fate and effect of 8-oxo-dG during transcription; repair mechanism may vary by situation and availability of repair enzymes at the time.

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 mechanism depends on the cell type,age of the cell and extra cellular environment.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The specific relationship between oxidative DNA lesions and when repair is regarded insufficient has yet to be determined; this relationship will most likely differ between cell types and tissues, making it difficult to define. There are computational models of 8-oxo-dG repair kinetics.

To explore the rate of clearance of BER repair intermediates, Sokhansanj and Wilson III [2004] used a quantitative model of BER and a literature estimate for the rate of generation of endogenous 8-oxo-dG (Sokhansanj and Wilson III, 2004).

The OGG1, AP lyases, polymerases, and ligases activities were incorporated in the BER model, which used Michaelis-Menten enzyme kinetics.
The model assumed that endogenous oxidative lesions formed at a rate of 500 8-oxo-dG/day.
- Based on the information above, it was calculated that after a sudden increase in 8-oxo-dG to 20,000 8-oxo-dG/cell, the total amount of repair intermediates would revert to baseline in 4000 seconds (less than 1 hour)
- This model also assumed that OGG1 was available in excess
The glycosylase reaction kinetics of OGG1 (a bifunctional glycosylase/lyase) were reported to increase when APE1 (AP site endonuclease) was present. It's thought to be because the two enzymes work together.
When OGG1 kinetics were reduced by tenfold, 8-oxo-dG increased tenfold, while no other repair intermediates increased.
Quantitative understanding is represented as below;

	Method/ measurement reference	Reliability	Strength of evidence	Assay fit for purpose	Repeatability/ reproducibility	Direct measure
Rat	Quantification of ATase activity – BSA method APNG assay, OXOG glycosylase activity assay, Western immunoblotting, Immunohistochemical detection of ATase (Kotova et al.,2013)	Yes	Strong	Yes	Yes	Yes
Rat cell line	Flow cytometric micronucleus assay, Cell cycle analysis, Replication fork elongation assay, Cytotoxicity assay, Recombination assay, (Panida et al.,2001)	Yes	Strong	Yes	Yes	Yes
mouse	FISH karyotyping, Invivo point mutation assay, Whole genome sequencing of HSC clones (Garayacoechea et al.,2012)	Yes	Strong	Yes	Yes	Yes

Response-response Relationship

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

Linear increase in DNA damage was noted following exposure to the stressor.

Time-scale

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

Changes were noted within 24 hours of treatment with the stressor, however after withdrawl of the stressor, persisted for 3-4 weeks.

The acute ethanol dose significantly inhibited O⁶-alkylguanine-DNA alkyltransferase (ATase) activity by 21–32% throughout the 24-h post-treatment period and this was confirmed by immunohistochemical detection of the ATase protein in hepatic nuclei. Twelve hours after the ethanol treatment, the activities of the DNA glycosylases, alkylpurine-DNA-N-glycosylase (APNG) and 8-oxoguanine-DNA glycosylase (OXOG glycosylase) were each increased by ~44%. In contrast, when given chronically via the liquid diet, ethanol initially had no effect on ATase activity, but after 4 weeks ATase activity was increased by 40%. Following ethanol withdrawal, ATase activity remained elevated for at least 12 h, but, by 24 h, the activity had fallen to the uninduced control level. DNA glycosylase activities were again affected differently. After 1 week of dietary ethanol exposure, there was no effect on APNG activity but it was inhibited by 19% at 4 weeks. OXOG glycosylase activity, on the other hand, was increased by 53% after 1 week, but decreased by 40% after 4 weeks.

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 found to the best of our knowledge.

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

In any eukaryotic or prokaryotic cell, oxidative DNA damage can develop and overwhelm the cell's repair processes. This KER has been seen in mammalian cells, yeast, and bacteria, among other places.

References

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

Allgayer, J., Kitsera, N., Bartelt, S., Epe, B., & Khobta, A. (2016). Widespread transcriptional gene inactivation initiated by a repair intermediate of 8-oxoguanine. Nucleic acids research, 44(15), 7267-7280.

Bellon, S., Shikazono, N., Cunniffe, S., Lomax, M., & O’Neill, P. (2009). Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic. Nucleic acids research, 37(13), 4430-4440.

Brenerman, B. M., Illuzzi, J. L., & Wilson III, D. M. (2014). Base excision repair capacity in informing healthspan. Carcinogenesis, 35(12), 2643-2652.

Budworth, H., Matthewman, G., O'Neill, P., & Dianov, G. L. (2005). Repair of tandem base lesions in DNA by human cell extracts generates persisting single-strand breaks. Journal of molecular biology, 351(5), 1020-1029.

Çağlayan, M., & Wilson, S. H. (2015). Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair. DNA repair, 35, 85-89.

Chinnasamy, N., Rafferty, J. A., Margison, G. P., O'CONNOR, P. J., & Elder, R. H. (1997). Induction of O 6-alkylguanine-DNA-alkyltransferase in the hepatocytes of rats following treatment with 2-acetylaminofluorene. DNA and cell biology, 16(4), 493-500.

Dahle, J., Brunborg, G., Svendsrud, D. H., Stokke, T., & Kvam, E. (2008). Overexpression of human OGG1 in mammalian cells decreases ultraviolet A induced mutagenesis. Cancer letters, 267(1), 18-25.

Delaney, S., Jarem, D. A., Volle, C. B., & Yennie, C. J. (2012). Chemical and biological consequences of oxidatively damaged guanine in DNA. Free radical research, 46(4), 420-441.

Freudenthal, B. D., Beard, W. A., & Wilson, S. H. (2013). DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion. Nucleic acids research, 41(3), 1848-1858.

Gagné, J. P., Rouleau, M., & Poirier, G. G. (2012). PARP-1 activation—bringing the pieces

together. Science, 336(6082), 678-679.

Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M., Arends, M. J., & Patel, K. J. (2012). Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature, 489(7417), 571-575.

Gehrke, T. H., Lischke, U., Gasteiger, K. L., Schneider, S., Arnold, S., Müller, H. C., ... & Carell, T. (2013). Unexpected non-Hoogsteen–based mutagenicity mechanism of FaPy-DNA lesions. Nature chemical biology, 9(7), 455-461.

Greenberg, M. M. (2012). The formamidopyrimidines: purine lesions formed in competition with 8-oxopurines from oxidative stress. Accounts of chemical research, 45(4), 588-597.

GROMBACHER, T., & KAINA, B. (1996). Isolation and analysis of inducibility of the rat N-methylpurine-DNA glycosylase promoter. DNA and cell biology, 15(7), 581-588.

Hashimoto, K., Tominaga, Y., Nakabeppu, Y., & Moriya, M. (2004). Futile short-patch DNA base excision repair of adenine: 8-oxoguanine mispair. Nucleic acids research, 32(19), 5928-5934.

Kotova, N., Vare, D., Schultz, N., Gradecka Meesters, D., Stępnik, M., Grawé, J., ... & Jenssen, D. (2013). Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair. Carcinogenesis, 34(2), 325-330.

Le Page, F., Klungland, A., Barnes, D. E., Sarasin, A., & Boiteux, S. (2000). Transcription coupled repair of 8-oxoguanine in murine cells: the ogg1 protein is required for repair in nontranscribed sequences but not in transcribed sequences. Proceedings of the National Academy of Sciences, 97(15), 8397-8402.

LEFEBVRE, P., ZAK, P., & LAVAL, F. (1993). Induction of O6-methylguanine-DNA-methyltransferase and N3-methyladenine-DNA-glycosylase in human cells exposed to DNA-damaging agents. DNA and cell biology, 12(3), 233-241.

Li, Y. S., Song, M. F., Kasai, H., & Kawai, K. (2013). Generation and threshold level of 8-OHdG as oxidative DNA damage elicited by low dose ionizing radiation. Genes and Environment.

Ma, H., Wang, J., Abdel-Rahman, S. Z., Boor, P. J., & Khan, M. F. (2008). Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline. Toxicology and applied pharmacology, 233(2), 247-253.

Maddukuri, L., Ketkar, A., Eddy, S., Zafar, M. K., & Eoff, R. L. (2014). The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa. Nucleic acids research, 42(19), 12027-12040.

Markkanen, E. (2017). Not breathing is not an option: How to deal with oxidative DNA damage. DNA repair, 59, 82-105.

Mitra, S., & Kaina, B. (1993). Regulation of repair of alkylation damage in mammalian genomes. Progress in nucleic acid research and molecular biology, 44, 109-142.

O’Connor, P. J. (1989). Towards a role for promutagenic lesions in carcinogenesis. In DNA repair mechanisms and their biological implications in mammalian cells (pp. 61-71). Springer, Boston, MA.

Navasumrit, P., Margison, G. P., & O'Connor, P. J. (2001). Ethanol modulates rat hepatic DNA repair functions. Alcohol and Alcoholism, 36(5), 369-376.

Pearson, C. G., Shikazono, N., Thacker, J., & O’Neill, P. (2004). Enhanced mutagenic potential of 8‐oxo‐7, 8‐dihydroguanine when present within a clustered DNA damage site. Nucleic acids research, 32(1), 263-270.

Potter, P. M., Rafferty, J. A., Cawkwell, L., Wilkinson, M. C., Cooper, D. P., O'Connor, P. J., & Margison, G. P. (1991). Isolation and cDNA cloning of a rat; O 6-alkyllguanine-DNA-alkyltransferase gene, molecelar analysis of expression in rat liver. Carcinogenesis, 12(4), 727-733.

Rafferty, J. A., Clarke, A. R., Sellappan, D., Koref, M. S., Frayling, I. M., & Margison, G. P. (1996). Induction of murine O6-alkylguanine-DNA-alkyltransferase in response to ionising radiation is p53 gene dose dependent. Oncogene, 12(3), 693-697.

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