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Relationship: 1910

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

Inadequate DNA repair leads to Increase, DNA strand breaks

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Inadequate DNA repair
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, DNA strand breaks

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 Do not cite WPHA/WNT Endorsed
Alkylation of DNA leading to reduced sperm count adjacent Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

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 NCBI
mouse Mus musculus NCBI
rat Rattus norvegicus NCBI

Sex Applicability

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

Life Stage Applicability

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

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

Inadequate repair of DNA damage includes incorrect repair (i.e., incorrect base insertion), incomplete repair (i.e., accumulation of repair intermediates such as strand breaks, stalled replications forks, and/or abasic sites), and absent repair resulting in the retention of DNA damage.

It is well-established that DNA excision repair pathways require DNA strand breakage for removing the damaged sites; for example, base excision repair (BER) of oxidative lesions involves removal of oxidized bases by glycosylases followed by cleavage of the DNA strand 5’ from the abasic site. If the repair process is disrupted at this point, repair intermediates including single strand breaks (SSB) may persist in the DNA. A SSB can turn into a double strand break (DSB) if it occurs sufficiently close to another SSB on the opposite strand. SSBs can be converted into DSBs when helicase unwinds the DNA strands during replication. Furthermore, SSBs and abasic sites can act as replication blocks causing the replication fork to stall and collapse, giving rise to DSBs (Minko et al., 2016; Whitaker et al., 2017).

The two most common DSB repair mechanisms are non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is may favoured over HR and has also been shown to be 104 times more efficient than HR in repairing DSBs (Godwin et al., 1994; Benjamin and Little, 1992). There are two subtypes of NHEJ: canonical NHEJ (C‐NHEJ) or alternative non-homologous end joining (alt-NHEJ). During C-NHEJ, broken ends of DNA are simply ligated together. In alt‐NHEJ, one strand of the DNA on either side of the break is resected to repair the lesion (Betermeir et al., 2014). Although both repair mechanisms are error‐prone (Thurtle‐Schmidt and Lo, 2018), alt-NHEJ is considered more error-prone than C-NHEJ (Guirouil-Barbat et al., 2007; Simsek and Jasin, 2010). While NHEJ may prevent cell death due to the cytotoxicity of DSBs, it may lead to mutations and genomic instability downstream.  

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

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
  • A variety of confounding factors and genetic characteristics (i.e., SNPs) may modulate which repair pathways are invoked and the degree to which they are inadequate. These have yet to be fully defined.
  • Both protective and damaging effects of OGG1 against strand breaks have been described in the literature. As demonstrated in the section above, the effect of OGG1-deficiency (BER-initiating enzyme) is observed to be different in different cell types; Wang et al. (2018) demonstrated strand breaks exacerbated by excessive OGG1 activity, while Wu et al. (2008) and Shah et al. (2018) demonstrated increased strand breaks due to lack of repair in mammalian cells in culture (Shah et al., 2018; Wu et al., 2008; Wang et al., 2018). Cell cycle and replication may influence the effect of DNA repair on exacerbating strand breaks. 
  • Dahle et al. (2008) exposed wild type and OGG1-overexpressing Chinese hamster ovary cells, AS52, to UVA. While OGG1-overexpression prevented the accumulation of Fpg-sensitive lesions (e.g., 8-oxo-dG and FaPyG) that were observed in wild type cells 4 hours after irradiation, there was no difference in the amount of strand breaks in the two cell types at 4h (Dahle et al., 2008). 
  • A recent study suggests that the NHEJ may be more accurate than previously thought (reviewed in Betermier et al., 2014). The accuracy of NHEJ may be dependent on the structure of the termini. The termini processing rather than the NHEJ itself is thus argued to be error-prone process (Betemier 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

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 applies to any cell type that has DNA repair capabilities.