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Increase, Oxidative DNA damage leads to Increase, Mutations
Key Event Relationship Overview
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||non-adjacent||High||Low||Brendan Ferreri-Hanberry (send email)||Open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages|
Key Event Relationship Description
Oxidative DNA lesions such as 7, 8-dihydro-8oxo-deoxyGuanine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FaPydG) are mutagenic because if they are not repaired they are able to form base pairs with dATP instead dCTP during replication. This can lead to permanent changes in the DNA sequence that is inherited by daughter cells with subsequent replication. G:C→T:A transversions are the most abundant base substitution attributed to oxidative DNA lesions (Cadet and Wagner, 2013).
Evidence Supporting this KER
Mutagenicity of oxidative DNA lesions has been extensively studied; incorrect base insertion opposite unrepaired oxidative DNA lesions during replication 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 with subsequent DNA synthesis (Gehrke et al., 2013; Freudenthal 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 for 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 often 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; Sha et al., 2017).
Uncertainties and Inconsistencies
The provided empirical evidence examined only the quantities of 8-oxo-dG and related the observed mutations to this oxidative lesion; the level of overall DNA oxidation is inferred from the level of 8-oxo-dG present. It is unclear how other oxidative DNA lesions such as FapyG, FapyA, and thymidine glycol contribute to the mutation spectra and frequencies.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
DNA in any cell type is susceptible to oxidative damage due to endogenous (e.g., aerobic respiration) and exogenous (i.e., exposure to oxidants) oxidative insults. Resulting increase in mutation frequency has been described in both eukaryotic and prokaryotic cells.
Cadet, J., Wagner, J.R. (2013), DNA Base Damage by Reactive Oxygen Species, Oxidizing Agents, and UV Radiation, Cold Spring Harb Perspect Biol, 5:a012559.
Freudenthal, B., Beard, W., Wilson, S. (2013), DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion., Nucleic Acids Res, 41:1848-1858.
Gehrke, T., Lischke, U., Gasteiger, K., Schneider, S., Arnold, S., Muller, H., Stephenson, D., Zipse, H., Carell, T. (2013), Unexpected non-Hoogsteen–based mutagenicity mechanism of FaPy-DNA lesions, Nat Chem Biol, 9:455-461.
Greenberg, M. (2012), Purine Lesions Formed in Competition With 8-Oxopurines From Oxidative Stress, Acc Chem Res, 45:588-597.
Hashimoto, K., Tominaga, Y., Nakabeppu, Y., Moriya, M. (2004), Futile short-patch DNA base excision repair of adenine:8-oxoguanine mispair, Nucleic Acids Res, 32:5928-5934.
Klungland, A., Rosewell, I., Hollenbach, S., Larsen, E., Daly, G., Epe, B., Seeberg, E., Lindahl, T., Barnes, D. (1999), Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage, Proc Natl Acad Sci USA, 96:13300-13305.
Maddukuri, L., Ketkar, A., Eddy, S., Zafar, M., Eoff, R. (2014), The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa, Nucleic Acids Res, 42:12027-12040.
Markkanen, E. (2017), Not breathing is not an option: How to deal with oxidative DNA damage, DNA Repair, 59:82-105.
Markkanen, E., Castrec, B., Vilani, G., Hubscher, U. (2012), A switch between DNA polymerases δ and λ promotes error-free bypass of 8-oxo-G lesions, Proc Natl Acad Sci USA, 27:931-940.
Platel, A., Nesslany, F., Gervais, V., Claude, N., Marzin, D. (2011), Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the thymidine kinase gene-mutation assay and the in vitro modified comet assay: Determination of No-Observed-Genotoxic-Effect-Levels, Mutat Res, 726:151-159.
Sha, Y., Minko, I., Malik, C., Rizzo, C., Lloyd, R.S. (2017), Error-Prone Replication Bypass of the Imidazole Ring-Opened Formamidopyrimidine Deoxyguanosine Adduct, Envrion Mol Mutatgen, 58:182-189.
Taggart, D., Fredrickson, S., Gadkari, V., Suo, Z. (2014), Mutagenic Potential of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass Catalyzed by Human Y-Family DNA Polymerases, Chem Res Toxicol, 27:931-940.
Takumi, S., Aoki, Y., Sano, T., Suzuki, T., Nohmi, T., Nohara, K. (2014), In vivo mutagenicity of arsenite in the livers of gpt delta transgenic mice , Mutat Res, 760:42-47.
Unfried, K., Schurkes, C., Abel, J. (2002), Distinct Spectrum of Mutations Induced by Crocidolite Asbestos: Clue for 8-Hydroxydeoxyguanosine-dependent Mutagenesis in Vivo, Cancer Res, 62:104.