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Increase, 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|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||High||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||High||Not Specified||Jessica Helm (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Mutations occur in one of two major ways: incorporation of an incorrect nucleotide leading to a point mutation, and incorrect rejoining of a double strand break leading to a deletion or other sequence change, homozygosity, or chromosomal damage. Mutations in surviving cells are then propagated to daughter cells.
Evidence Supporting this KER
Biological Plausibility is High. DNA damage in the form of nucleotide damage, single strand and double strand breaks, and complex damage can generate mutations, particularly when a damaged cell undergoes replication.
Empirical Support is High. It is generally accepted that DNA damage leads to mutations. Empirical support comes in part from the observation that agents which increase DNA damage also cause mutations, that DNA damage precedes the appearance of mutations, and that interventions that reduce DNA damage also reduce mutations. None of the identified studies measure both outcomes over the same range of time points. This constitutes a readily addressable data gap.
High. DNA damage in the form of nucleotide damage, single strand and double strand breaks, and complex damage can generate mutations, particularly when a damaged cell undergoes replication.
Damage to single nucleotides can generate mutations. Oxidative damage and ionizing radiation can induce a range of base lesions, but guanine is particularly vulnerable because of its low redox potential (David, O'Shea et al. 2007). Repair is generally accurate, but generates single strand breaks. Repair processes can also insert an incorrect nucleotide where a lesion has been excised. If not corrected by mismatch repair processes before a replication cycle, an incorrect base is matched with its pair and is made permanent (Tubbs and Nussenzweig 2017). In a cell undergoing replication, the replication fork typically stalls at a lesion until repairs are complete, but translesion synthesis allows the replication fork to proceed at the cost of increased errors, or mutations (Abbotts and Wilson 2017). Different lesions vary in their frequency and ability to escape repair or be replicated and incorrectly paired by DNA polymerase, making some lesions more mutagenic than others. For example, guanine lesion 8-oxoguanine is very common, so although it is efficiently repaired it contributes to guanine mutations. Other guanine lesions including Fapy and hydantoins are less common but very mutagenic, so likely also contribute to guanine mutations (Neeley and Essigmann 2006; David, O'Shea et al. 2007). Thymine glycol is another common oxidative lesion formed from thymine that can also generate mutations.
Single strand breaks are generally repaired efficiently through a variant of the base excision repair pathway. However, replication fork collapse can occur when the replisome encounters an unrepaired single strand break, resulting in a double strand break (Kuzminov 2001).
Double strand breaks can generate mutations ranging from point mutations to inversions, deletions, duplications, and chromosomal gaps, breaks, and micronuclei. Double strand breaks can be repaired via two to three major pathways depending on damage type and cell stage among other conditions, and the mutation type and frequency depends on the repair mechanism employed.
Double strand breaks generated from the stalling or collapse of replication forks around lesions or single strand break are processed using homologous recombination (HR) (Rothkamm and Lobrich 2003; Ceccaldi, Rondinelli et al. 2016). Because these breaks happen during replication, an identical sister chromatid may be present to use as a template and repair can restore the original sequence. However, HR can also occur using a non-sister chromatid or in the case of repeated regions can use another stretch of DNA as a template, resulting in loss of homozygosity, inversions, deletions, and duplications (Saleh-Gohari, Bryant et al. 2005; Shrivastav, De Haro et al. 2008). HR may also increase point mutations (Shrivastav, De Haro et al. 2008).
Double strand breaks occurring in all parts of the cell cycle may be processed by non-homologous end joining (NHEJ) (Rothkamm and Lobrich 2003), which can alter the nucleotide sequence of the two broken ends to achieve a fusible template leading to point mutations, deletions, and insertions (Ceccaldi, Rondinelli et al. 2016). NHEJ can fuse incorrect ends within or between chromosomes, resulting in major changes including translocations, deletions, inversions, and duplications. Compared with HR, NHEJ is considered to be more likely to generate mutations, particular the resection dependent classical or alternative end joining pathways (Ceccaldi, Rondinelli et al. 2016).
Complex damage delays repair and increases double strand breaks, increasing the likelihood of mutation. Clustered lesions or single strand breaks are processed more slowly than non-clustered lesions, increasing the number of lesions that will undergo replication and potentially generate mutations in daughter cells (Dianov, Timchenko et al. 1991; Eccles, O'Neill et al. 2011). Clustered damage made of closely opposed lesions and/or single strand breaks can also create double strand breaks (Chaudhry and Weinfeld 1997; Vispe and Satoh 2000; Yang, Galick et al. 2004; Schipler and Iliakis 2013; Sharma, Collins et al. 2016; Shiraishi, Shikazono et al. 2017). Complex damage involving double strand breaks is also repaired more slowly (Stenerlow, Hoglund et al. 2000; Schipler and Iliakis 2013; Lorat, Timm et al. 2016), and undergoes a form of NHEJ with excision that leads to increased translocations and deletions (Eccles, O'Neill et al. 2011; Sharma, Collins et al. 2016; Watts 2016).
Genomic instability is the prolonged appearance of DNA damage, chromosomal damage, and mutations. It is sometimes seen following agents that induce DNA damage including ionizing radiation, RONS, and NMU (Goepfert, Moreno-Smith et al. 2007; Kadhim, Salomaa et al. 2013; Stanicka, Russell et al. 2015). DNA damage occurring during genomic instability is associated with the appearance of mutations including deletions, inversions, and duplications (Murnane 2012; Kadhim, Salomaa et al. 2013; Sishc, Nelson et al. 2015).
Uncertainties and Inconsistencies
Despite the generally accepted relationship between DNA damage and mutations, few studies uncovered in the literature for RONS or ionizing radiation measure both DNA damage and mutations in the same study (Denissova, Nasello et al. 2012; Sharma, Collins et al. 2016; Biehs, Steinlage et al. 2017) and none measure both key events at the same time points.
Mutations generally increase linearly with dose of DNA damaging agents (Sandhu and Birnboim 1997; Sharma, Collins et al. 2016), but multiple factors including DNA repair, bystander effects, and genomic instability can affect the shape of the dose-response. IR promotion of DNA repair mechanisms decrease major mutations (lethal recessive changes) at lower IR doses/dose rates in flies (0.2 Gy at 0.05 Gy/min gamma) (Koana and Tsujimura 2010). In contrast, non-targeted effects of IR contribute to supralinear responses at lower doses (Sandhu and Birnboim 1997; Hall and Hei 2003; Yang, Anzenberg et al. 2007). At higher doses (10-80 Gy) rearrangements from misrejoining (joining together of non-sequential DNA) increase linearly with dose for high LET IR, but supralinearly for low LET IR, attributed to the increase in the concentration and complexity of double strand breaks with LET (Rydberg, Cooper et al. 2005).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Biehs, R., M. Steinlage, et al. (2017). "DNA Double-Strand Break Resection Occurs during Non-homologous End Joining in G1 but Is Distinct from Resection during Homologous Recombination." Molecular cell 65(4): 671-684 e675.
Buonanno, M., S. M. de Toledo, et al. (2011). "Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress." Radiation research 175(4): 405-415.
Chaudhry, M. A. and M. Weinfeld (1997). "Reactivity of human apurinic/apyrimidinic endonuclease and Escherichia coli exonuclease III with bistranded abasic sites in DNA." The Journal of biological chemistry 272(25): 15650-15655.
Choi, K. M., C. M. Kang, et al. (2007). "Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK." Oncol Rep 17(5): 1183-1188.
Denissova, N. G., C. M. Nasello, et al. (2012). "Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage." Carcinogenesis 33(1): 149-155.
Dianov, G. L., T. V. Timchenko, et al. (1991). "Repair of uracil residues closely spaced on the opposite strands of plasmid DNA results in double-strand break and deletion formation." Molecular & general genetics : MGG 225(3): 448-452.
Koana, T. and H. Tsujimura (2010). "A U-shaped dose-response relationship between x radiation and sex-linked recessive lethal mutation in male germ cells of Drosophila." Radiation research 174(1): 46-51.
Kuzminov, A. (2001). "Single-strand interruptions in replicating chromosomes cause double-strand breaks." Proceedings of the National Academy of Sciences of the United States of America 98(15): 8241-8246.
Lorat, Y., S. Timm, et al. (2016). "Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation." Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 121(1): 154-161.
Padula, G., M. V. Ponzinibbio, et al. (2016). "Possible radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro." Indian J Exp Biol 54(8): 537-543.
Rothkamm, K. and M. Lobrich (2003). "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses." Proceedings of the National Academy of Sciences of the United States of America 100(9): 5057-5062.
Rydberg, B., B. Cooper, et al. (2005). "Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation." Radiation research 163(5): 526-534.
Saleh-Gohari, N., H. E. Bryant, et al. (2005). "Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks." Molecular and cellular biology 25(16): 7158-7169.
Schipler, A. and G. Iliakis (2013). "DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice." Nucleic acids research 41(16): 7589-7605.
Seager, A. L., U. K. Shah, et al. (2012). "Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance." Toxicological sciences : an official journal of the Society of Toxicology 128(2): 387-397.
Stanicka, J., E. G. Russell, et al. (2015). "NADPH oxidase-generated hydrogen peroxide induces DNA damage in mutant FLT3-expressing leukemia cells." The Journal of biological chemistry 290(15): 9348-9361.
Yang, N., H. Galick, et al. (2004). "Attempted base excision repair of ionizing radiation damage in human lymphoblastoid cells produces lethal and mutagenic double strand breaks." DNA repair 3(10): 1323-1334.