API

Relationship: 1897

Title

?

Increase, DNA Damage leads to Increase, Mutations

Upstream event

?

Increase, DNA Damage

Downstream event

?


Increase, Mutations

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Adjacency Weight of Evidence Quantitative Understanding
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent High Not Specified
Increased DNA damage leading to increased risk of breast cancer adjacent High Not Specified

Taxonomic Applicability

?

Sex Applicability

?

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.

 

Biological Plausibility

?

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.

Nucleotide damage

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

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

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

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/Long term effects

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).

Empirical Evidence

?

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.

Ionizing radiation (IR) and reactive oxygen and nitrogen species (RONS) are both capable of causing DNA damage including lesions, single and double strand breaks, and these agents also cause mutations (Schiestl, Khogali et al. 1994; Kuhne, Rothkamm et al. 2000; Rydberg, Cooper et al. 2005; Dayal, Martin et al. 2008; Seager, Shah et al. 2012), and chromosomal aberrations (Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Du, Gao et al. 2009; Buonanno, de Toledo et al. 2011; Patil, Rao et al. 2014; Fetisova, Antoschina et al. 2015; Padula, Ponzinibbio et al. 2016). DNA damage observed after IR and RONS precedes the appearance of mutations (Denissova, Nasello et al. 2012; Sharma, Collins et al. 2016) and precedes or is concordant with the appearance of chromosomal aberrations (Yang, Asaad et al. 2005; Du, Gao et al. 2009; Suzuki, Kashino et al. 2009; Patil, Rao et al. 2014; Padula, Ponzinibbio et al. 2016). Further evidence that mutations arise from DNA damage comes from agents that affect DNA repair: decreasing repair after IR maintains damage while decreasing translocations (mutations introduced by DNA repair) (Biehs, Steinlage et al. 2017).

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.

Quantitative Understanding of the Linkage

?


Response-response Relationship

?

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).

Time-scale

?

Known modulating factors

?

Known Feedforward/Feedback loops influencing this KER

?

Domain of Applicability

?


References

?


Abbotts, R. and D. M. Wilson, 3rd (2017). "Coordination of DNA single strand break repair." Free radical biology & medicine 107: 228-244.

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.

Ceccaldi, R., B. Rondinelli, et al. (2016). "Repair Pathway Choices and Consequences at the Double-Strand Break." Trends in cell biology 26(1): 52-64.

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.

David, S. S., V. L. O'Shea, et al. (2007). "Base-excision repair of oxidative DNA damage." Nature 447(7147): 941-950.

Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.

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.

Du, C., Z. Gao, et al. (2009). "Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts." Cancer Biol Ther 8(20): 1962-1971.

Eccles, L. J., P. O'Neill, et al. (2011). "Delayed repair of radiation induced clustered DNA damage: friend or foe?" Mutation research 711(1-2): 134-141.

Fetisova, E. K., M. M. Antoschina, et al. (2015). "Radioprotective effects of mitochondria-targeted antioxidant SkQR1." Radiation research 183(1): 64-71.

Goepfert, T. M., M. Moreno-Smith, et al. (2007). "Loss of chromosomal integrity drives rat mammary tumorigenesis." Int J Cancer 120(5): 985-994.

Hall, E. J. and T. K. Hei (2003). "Genomic instability and bystander effects induced by high-LET radiation." Oncogene 22(45): 7034-7042.

Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.

Kadhim, M., S. Salomaa, et al. (2013). "Non-targeted effects of ionising radiation--implications for low dose risk." Mutation research 752(2): 84-98.

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.

Kuhne, M., K. Rothkamm, et al. (2000). "No dose-dependence of DNA double-strand break misrejoining following alpha-particle irradiation." International journal of radiation biology 76(7): 891-900.

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.

Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.

Neeley, W. L. and J. M. Essigmann (2006). "Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products." Chemical research in toxicology 19(4): 491-505.

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.

Patil, S. L., N. B. Rao, et al. (2014). "Antigenotoxic potential of rutin and quercetin in Swiss mice exposed to gamma radiation." Biomed J 37(5): 305-313.

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.

Sandhu, J. K. and H. C. Birnboim (1997). "Mutagenicity and cytotoxicity of reactive oxygen and nitrogen species in the MN-11 murine tumor cell line." Mutation research 379(2): 241-252.

Schiestl, R. H., F. Khogali, et al. (1994). "Reversion of the mouse pink-eyed unstable mutation induced by low doses of x-rays." Science 266(5190): 1573-1576.

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.

Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.

Shiraishi, I., N. Shikazono, et al. (2017). "Efficiency of radiation-induced base lesion excision and the order of enzymatic treatment." International journal of radiation biology 93(3): 295-302.

Shrivastav, M., L. P. De Haro, et al. (2008). "Regulation of DNA double-strand break repair pathway choice." Cell Res 18(1): 134-147.

Sishc, B. J., C. B. Nelson, et al. (2015). "Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis." Front Oncol 5: 257.

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.

Stenerlow, B., E. Hoglund, et al. (2000). "Rejoining of DNA fragments produced by radiations of different linear energy transfer." International journal of radiation biology 76(4): 549-557.

Suzuki, K., G. Kashino, et al. (2009). "Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells." Mutation research 671(1-2): 33-39.

Tubbs, A. and A. Nussenzweig (2017). "Endogenous DNA Damage as a Source of Genomic Instability in Cancer." Cell 168(4): 644-656.

Vispe, S. and M. S. Satoh (2000). "DNA repair patch-mediated double strand DNA break formation in human cells." The Journal of biological chemistry 275(35): 27386-27392.

Watts, F. Z. (2016). "Repair of DNA Double-Strand Breaks in Heterochromatin." Biomolecules 6(4).

Yang, H., V. Anzenberg, et al. (2007). "The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts." Radiation research 168(3): 292-298.

Yang, H., N. Asaad, et al. (2005). "Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts." Oncogene 24(12): 2096-2103.

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.