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Relationship: 1909

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

Increase, Oxidative DNA damage leads to Inadequate DNA repair

Upstream event

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

Increase, Oxidative DNA damage

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
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 Do not cite	WPHA/WNT Endorsed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 occurrence of cataracts	adjacent	Moderate	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
human	Homo sapiens	Moderate	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Low	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

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

Term	Evidence
All life stages	Moderate

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

Oxidative DNA lesions are present in the cell at steady state due to low levels of reactive oxygen species (ROS) and other free radicals generated by endogenous processes involving redox reactions. The most prominent examples of 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 conditions, cells are able to regulate the level of free radicals and readily repair oxidized DNA bases using basal repair mechanisms to prevent irreversible 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. Abasic sites are then cleaved by endonucleases or lyases, resulting in transient single-strand breaks (SSB) that enter either short-patch or long-patch repair. Nucleotide excision repair (NER) is also involved in repairing oxidized bases to a lesser extent (Shafirovich et al., 2016). Increase in free radicals or exposure to oxidizing agents can increase the level of oxidative DNA lesions and overwhelm the repair pathways, compromising the quality of repair. If the repair mechanisms are compromised, oxidative lesions may accumulate (insufficient repair) and cause incorrect base pairing during replication or incomplete repair (indicated by accumulation of repair intermediates) (Markkanen, 2017).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Although the dual functionality of OGG1 as a glycosylase and lyase has been widely accepted and demonstrated experimentally, there are studies showing that the cleavage of phosphodiester bond 5’ to the lesion is mainly performed by apurinic endonuclease 1 (APE1) (Allgayer et al., 2016; R. Wang et al., 2018). In some cases, APE1 may be the main factor driving the accumulation of BER intermediates. Some studies suggest that OGG1 is involved in the repair of non-transcribed strands and is not required for transcription-coupled repair of 8-oxo-dG; 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). Moreover, the repair of 8-oxo-dG is also affected by the neighbouring sequence; the position of the lesions may have a negative effect on repair efficiency (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

N/A

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)

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 precise relationship between levels of oxidative DNA lesions and when repair can be considered inadequate have not been fully defined; this relationship will very likely differ between cell types and tissues and, thus, difficult to define. There are computational models of repair kinetics of 8-oxo-dG.

Sokhansanj and Wilson III [2004] applied a quantitative model of BER and the literature value for the rate of formation of endogenous 8-oxo-dG to investigate the rate of clearance of BER repair intermediates (Sokhansanj and Wilson III, 2004).

The BER model used Michaelis-Menten enzyme kinetics and included the activities of OGG1, AP lyases, polymerases, and ligases.
The model assumed the formation rate of endogenous oxidative lesions to be 500 8-oxo-dG/day
Based on the above, it was estimated that following a sudden spike in 8-oxo-dG up to 20,000 8-oxo-dG/cell, the total level of repair intermediates would return to baseline within 4000 seconds (less than 1 hour)
- This model also assumed that OGG1 was available in excess
When APE1 (AP site endonuclease) is present, glycosylase reaction kinetics of OGG1(a bifunctional glycosylase/lyase) was observed to increase
- Suggested to be due to the coordinated action of the two enzymes
A 10-fold reduction in OGG1 kinetics led to 10-fold increase in 8-oxo-dG, while no other repair intermediates increased.

Response-response Relationship

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

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

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

N/A

Domain of Applicability

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

This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from in vivo mice studies of all ages with no specification on sex. No in vitro evidence was found to support the relationship.