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Relationship: 2817

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 Cataracts

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Deposition of energy leading to occurrence of cataracts non-adjacent Low Low Vinita Chauhan (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 Do not cite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 Low 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
Mixed 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

Inadequate repair of DNA is the inability for the cell’s repair machinery to properly maintain correct DNA structure and sequences following the creation of errors (Helleday et al., 2008; Massey & Jones, 2018). Cataracts are herein considered to be the opacification of the lens, and are associated within a reduction in visual acuity (Moreau & King, 2012). DNA repair has several different pathways when functioning correctly. Pathway examples include base excision repair (BER), non-homologous end-joining (NHEJ), nucleotide-excision repair (NER), homologous recombination (HR), and single-strand break repair (SSBR). These pathways are triggered to start when their specific type of DNA lesion is detected (Helleday et al., 2008). Some of these pathways, like NHEJ, are considered to be error-prone (Chiruvella et al., 2013; Hamada & Fujimichi, 2015). The dysregulation and breakdown of these pathways results in the cell having an accumulation of DNA damage (Massey & Jones, 2018). This accumulated genomic damage can lead to improper cellular morphology in lens cells leading to cataracts (Worgul et al., 1989).  

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 Supporting this KER

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

Overall Weight of Evidence: Low 

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

The biological plausibility of the relationship between inadequate DNA repair leading to cataracts is moderately supported by the literature (Kleiman 2013, Hall et al. 2005, Ainsbury et al. 2021, Hamada 2017, Hamada et al. 2015, Blakely et al. 2010, Dauer et al. 2014, Ainsbury et al. 2009, Foray et al. 2016, NCRP 2016, ICRP 2012, Kleiman 2012). Mouse models have been used to support this connection, with all listed ages below 3 months old (Worgul et al., 2002; Worgul et al., 2005; Hall et al., 2006; Kleiman et al., 2007; McCarron et al., 2021). Humans have higher levels of repair enzyme-coding gene expression than mice, and most human repair pathways are more sufficiently activated (MacRae et al., 2015).  

Cataracts may be at increased risk of development following the cell’s inability to properly repair DNA damage. High levels of single-strand DNA damage have been seen in the epithelial cells of cataract patients (Kleiman & Spector, 1993). Epithelial cells with DNA damage typically have elevated levels of p21, implying an inability to breakdown the nuclear envelope of the cell. This impedes lens epithelial cell differentiation into proper lens fiber cells, contributing to cataract incidence (Siddam et al., 2018; NCRP, 2016; Worgul et al., 1989). Lens fiber cells typically have a dissolved nuclear envelope and no organelles, this is because, these structures interfere with light scattering, which is essential for the proper functioning of the lens. Furthermore, when the nuclear envelope is not dissolved, as in cases of aberrant differentiation, it presents an opportunity for light to scatter, reducing visual acuity (Siddam et al., 2018; Moreau & King, 2012). This becomes problematic as lens cells are not replaced, so any damage sustained will accumulate, potentially leading to cataracts (Toyama & Hetzer, 2013). The complete understanding of this process is still needed (Worgul et al., 1991; Barnard et al., 2018). Haploinsufficiency is a large contributor to inadequate DNA repair resulting in cataract formation (Kleiman, 2007). Genes such as Mrad9, Brca1, and ATM are important for the proper functioning of DNA repair machinery s, and by acting as cell cycle checkpoints (ICRP, 2012; Foray et al., 2016; Hamada & Fujimichi, 2015; Blakely et al., 2010; Hamada, 2017; Dauer et al., 2014). When these genes are heterozygous in an organism, this raises the risk of haploinsufficiency (Kleiman, 2007). Individuals that are haploinsufficient in these genes have a higher likelihood of developing cataracts (Foray et al., 2016; Kleiman, 2007; Hamada & Fujimichi, 2015; ICRP, 2012). This is because genetic susceptibility to cataracts is partially contingent on repair deficits developing (Blakely et al., 2010; Kleiman, 2012; Ainsbury et al., 2009). The inability to adequately repair DNA damage in the lens epithelium can cause genomic damage retention, which can then lead to cataract development (ICRP, 2012). It has also been shown that the presence of heterozygosity in two genes, where one is ATM and the other is either Mrad9 or Braca1, increases the risk of cataracts more than heterozygosity in just one of the genes (Blakely et al., 2010; NCRP, 2016; ICRP, 2012). The Ercc2 gene is responsible for nucleotide excision repair (Weber et al., 1988). Ercc2 heterozygous B6C3F1 mice experience significant effects on mean and maximum opacity. Female mice have a higher risk of cataracts, as well as experiencing an estrogen-implicated increase in speed of cataract progression (McCarron et al., 2021). Furthermore, some genetic disorders that relate heavily to impaired repair function, such Cockanye syndrome and trichothiodystrophy, have cataract development as a symptom of the condition (Dollfus et al., 2003). 

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

N/A

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
Genetics Ptch1  Heterozygosity for Ptch1 increases cataract susceptibility, particularly after exposure to higher radiation doses.  De Stefano et al., 2014; De Stefano et al., 2016; Tanno et al., 2022 
Genetics ATM Humans carrying the A allele of ATM rs189037 had increased cataract risk.  Gao et al., 2022 
Genetics TP53 Humans carrying the C allele of TP53 had increased cataract risk.  Gao et al., 2022 
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 and requiring a clear lens for vision. The majority of the evidence is from in vivo adult mice and does not specify sex and weanling mice in vitro models that do not specify sex. 

References

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

Ainsbury, E. et al. (2021), “Radiation-induced lens opacities: Epidemiological, clinical and experimental evidence, methodological issues, research gaps and strategy”, Environment International, Vol.146, Elsevier Ltd, London, https://doi.org/10.1016/j.envint.2020.106213.  

Ainsbury, E. et al. (2009), “Radiation Cataractogenesis: A Review of Recent Studies”, Radiation Research, Vol.172/1, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR1688.1. 

Amador, V. et al. (2007), “APC/C (Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase”, Molecular Cell, Vol.27, Cell Press, Cambridge, https://doi.org/10.1016/J.MOLCEL.2007.06.013. 

Bakkenist, C.J. and M.B. Kastan. (2003), “DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation”, Nature, Vol.421, Nature Portfolio, London, https://doi.org/10.1038/nature01368. 

Blakely, E. et al. (2010), “Radiation Cataractogenesis: Epidemiology and Biology”, Radiation Research, Vol.173/5, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RRXX19.1. 

Chen, M.J. et al. (2001), “ATM-dependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation”, Journal of Biological Chemistry, Vol.276, American Society for Biochemistry and Molecular Biology, Rockville, https://doi.org/10.1074/JBC.M008871200. 

Chiruvella, K., Z. Liang and T. Wilson. (2013), “Repair of double-strand breaks by end joining”, Cold Spring Harbor Perspectives in Biology, Vol.5, Cold Spring Harbor Laboratory Press, Long Island, https://doi.org/10.1101/cshperspect.a012757. 

Dauer, L. et al. (2014), “Epidemiology and Mechanistic Effects of Radiation on the Lens of the Eye: Review and Scientific Appraisal of the Literature”, EPRI Technical Report, Vol.2014, Electric Power Research Institute, Palo Alto. 

De Stefano, I. et al. (2014), “The patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract”, American Society for Investigative Pathology, Vol. 185/1, Elsevier, https://doi.org/10.1016/j.ajpath.2014.09.019 

De Stefano, I. et al. (2016), “Nonlinear radiation-induced cataract using the radiosensitive Ptch1(+/-) mouse model”, Radiation Research, Vol. 186/3, BioOne, https://doi.org/10.1667/RR14440.1 

Dollfus, H. et al. (2003), “Ocular Manifestations in the Inherited DNA Repair Disorders”, Survey of Ophthalmology, Vol.48/1, Elsevier, Amsterdam, https://doi.org/10.1016/S0039-6257(02)00400-9. 

Foray, N., M. Bourguignon and N. Hamada. (2016), “Individual response to ionizing radiation”, Mutation Research - Reviews in Mutation Research, Vol.770, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrrev.2016.09.001. 

Fragkos, M., J. Jurvansuu and P. Beard. (2009), “H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway”, Molecular and Cellular Biology, Vol.29/10, American Society for Microbiology, Washington, https://doi.org/10.1128/MCB.01830-08. 

Gao, Y. et al. (2022), “ATM and TP53 polymorphisms modified susceptibility to radiation-induced lens opacity in natural high background radiation area, China”, International Journal of Radiation Biology, Vol. 98/7, https://doi.org/10.1080/09553002.2022.2024294 

Hall, E. et al. (2006), “The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene”, Radiation and Environmental Biophysics, Vol.45/2, Springer, New York, https://doi.org/10.1007/S00411-006-0052-5.  

Hall, E. et al. (2005), “Genetic susceptibility to radiation”, Advances in Space Research, Vol.35/2, Elsevier Ltd, London, https://doi.org/10.1016/J.ASR.2004.12.032. 

Hamada, N. (2017), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International Journal of Radiation Biology, Vol.93/10, Informa, London, https://doi.org/10.1080/09553002.2016.1266407. 

Hamada, N. and Y. Fujimichi. (2015), “Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis”, Cancer Letters, Vol.368/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2015.02.017.  

Helleday, T. et al. (2008), “DNA repair pathways as targets for cancer therapy”, Nature Reviews Cancer, Vol.8/3, Nature Portfolio, London, https://doi.org/10.1038/nrc2342. 

ICRP (2012), “ICRP Publication #118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs - Threshold Doses for Tissue Reactions in a Radiation Protection Context”, Annals of the ICRP, Vol.41/1-2, Elsevier, Amsterdam, https://doi.org/10.1016/j.icrp.2012.02.001. 

Insinga, A. et al. (2013), “DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions”, PNAS, Vol.110/10, National Academy of Sciences, Washington, https://doi.org/10.1073/pnas.1213394110. 

Jiricny, J. and G. Marra. (2003), “DNA repair defects in colon cancer”, Current Opinion in Genetics and Development, Vol.13/1, Elsevier Ltd, London, https://doi.org/10.1016/S0959-437X(03)00004-2. 

Kleiman, N.J. (2013), “Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity”, Columbia University, New York, https://doi.org/10.2172/1124670. 

Kleiman, N.J. (2012), “Radiation cataract”, Annals of the ICRP, Vol.41/3-4, Elsevier, Amsterdam, https:/doi.org/10.1016/j.icrp.2012.06.018.  

Kleiman, N.J. et al. (2007), “Mrad9 and Atm Haploinsufficiency Enhance Spontaneous and X-Ray-Induced Cataractogenesis in Mice”, Radiation Research, Vol.168/5, Radiation Research Society, Indianapolis, https://doi.org/10.1667/rr1122.1.  

Kleiman, N.J. and A. Spector. (1993), “DNA single strand breaks in human lens epithelial cells from patients with cataract”, Current Eye Research, Vol.12, Taylor & Francis, Oxfordshire, https://doi.org/10.3109/02713689309024624. 

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306 

Lee, J.H. and T.T. Paull. (2007), “Activation and regulation of ATM kinase activity in response to DNA double-strand breaks”, Oncogene, Vol.26/56, Nature Portfolio, London, https://doi.org/10.1038/sj.onc.1210872. 

MacRae, S. L. et al. (2015), “DNA repair in species with extreme lifespan differences”, Aging, Vol.7/12, Impact Journals, New York, https://doi.org/10.18632/AGING.100866. 

Massey, T.H. and L. Jones. (2018), “The central role of DNA damage and repair in CAG repeat diseases”, Disease Models and Mechanisms, Vol.11/1, The Company of Biologists, Cambridge, https://doi.org/10.1242/dmm.031930. 

McCarron, R. et al. (2021), “Radiation-Induced Lens Opacity and Cataractogenesis: A Lifetime Study Using Mice of Varying Genetic Backgrounds”, Radiation Research, Vol.196, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RADE-20-00266.1. 

Moreau, K. and J. King. (2012), “Protein misfolding and aggregation in cataract disease and prospects for prevention”, Trends in Molecular Medicine, Vol.18/5, Elsevier Ltd, London, https://doi.org/10.1016/j.molmed.2012.03.005. 

NCRP (2016), “Guidance on radiation dose limits for the lens of the eye”, NCRP Commentary, Vol.26, National Council on Radiation Protection and Measurements Publications, Bethesda. 

Siddam, A.D. et al. (2018), “The RNA-binding protein Celff1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development”, PLOS Genetics, Vol.14/3, PLOS, San Francisco, https://doi.org/10.1371/journal.pgen.1007278. 

Smilenov, L. et al. (2005), “Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics”, Cancer Research, Vol.65/3, American Association for Cancer Research, Philadelphia, https://doi.org/10.1158/0008-5472.933.65.3. 

Takayama, K. et al. (1995), “Defects in DNA Repair and Transcription Gene ERCC2 in the Cancer-prone Disorder Xeroderma Pigmentosum Group D”, Cancer Research, Vol.55/23, American Association for Cancer Research, Philadelphia, pp.5656–5663. 

Tanno, B. et al. (2022), “miRNA-signature of irradiated Ptch1+/- mouse lens is dependent on genetic background”, Radiation Research, Vol. 197/1, https://doi.org/10.1667/RADE-20-00245.1 

Toyama, B. and M. Hetzer. (2013), “Protein homeostasis: Live long, won't prosper”, Nature Reviews Molecular Cell Biology, Vol.14/1, Nature Portfolio, London, https://doi.org/10.1038/nrm3496

Turesson, I. et al. (2003), “Biological Response to Radiation Therapy”, Acta Oncologica, Vol.42/2, Taylor & Francis, Oxfordshire, https://doi.org/10.1080/02841860310004959. 

Udroiu, I. et al. (2020), “DNA damage in lens epithelial cells exposed to occupationally-relevant X-ray doses and role in cataract formation”, Scientific Reports, Vol.10, Nature Portfolio, London, https://doi.org/10.1038/s41598-020-78383-2. 

Weber, C.A. et al. (1988), “Molecular cloning and biological characterization of a human gene, ERCC2, that corrects the nucleotide excision repair defect in CHO UV5 cells”, Molecular and Cellular Biology, Vol.8/3, American Society for Microbiology, Washington, https://doi.org/10.1128/mcb.8.3.1137-1146.1988. 

Worgul, B. et al. (2005), “Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes”, Advances in Space Research, Vol.35/2, Elsevier Ltd, London, https://doi.org/10.1016/J.ASR.2005.01.030.  

Worgul, B. et al. (2002), “Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts”, PNAS, Vol.99/15, National Academy of Sciences, Washington, https://doi.org/10.1073/pnas.162349699.  

Worgul, B. et al. (1991), “Evidence of genotoxic damage in human cataractous lenses”, Mutagenesis, Vol.6/6, Oxford University Press, Oxford, https://doi.org/10.1093/MUTAGE/6.6.495.  

Worgul, B.V., C. Medvedovsky and G.R. Merriam. (1989), “Cortical cataracts development-the expression of primary damage to the lens epithelium”, Lens Eye Toxicity Research, Vol.6, Marcel Dekker, New York, pp557-571.