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Inadequate DNA repair leads to Cataracts
Key Event Relationship Overview
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 Do not cite|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
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
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
Overall Weight of Evidence: Low
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
Known modulating factors
|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|
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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