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Increase, DNA strand breaks 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 Do not cite||EAGMST Under Review|
|Direct deposition of ionizing energy leading to lung cancer||non-adjacent||High||Low||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
DNA single strand breaks (SSB) are generally repaired rapidly and efficiently. However, if left unrepaired, SSBs can interfere with replication and cause the replication fork to collapse resulting in double strand breaks (DSB). Multiple SSBs in close proximity to each other can also give rise to DSBs. DSBs can be repaired virtually error-free by homologous recombination (HR), which uses DNA sequence in the homologous chromosome or sister chromatid as a template for new strand synthesis (Polo and Jackson, 2011). Alternatively, the broken ends may be joined to other sites in the genome regardless of homology via non-homologous end joining (NHEJ), irreversibly altering the DNA sequence (deletion, addition, rearrangement). Because HR is a more time-consuming and labour-intensive process, larger proportions of DSBs are repaired via NHEJ than via HR (Mao et al., 2008a; Mao et al., 2008b).
Alterations in DNA sequence can also occur from structural damage to the chromosomes; observations of micronucleus indicate chromosomal aberrations and that a permanent loss of DNA segments has occurred.
Evidence Supporting this KER
The mechanisms by which strand breaks lead to mutations are very well studied and understood. Thus, we provide a small selection of empirical evidence below supporting this KER; i.e., we did not undertake and exhaustive literature search.
The error-prone nature of DSB repair in eukaryotes has been described in numerous reviews. In mammalian and yeast cells, both HR and NHEJ can lead to alteration in DNA sequence; insertions, deletions, and translocations can arise from NHEJ and base substitutions can occur during the repair synthesis of HR (Hicks and Haber, 2010; Bunting and Nussenzweig, 2013; Byrne et al., 2014; Rodgers and McVey, 2016; Dwivedi and Haber, 2018).
Uncertainties and Inconsistencies
In Kuhne et al. (2005) and Rydberg et al. (2005) studies provided above, mutation was not directly measured. The PFGE and hybridization assay detects a 3.2-Mbp restriction fragment from chromosome 21. Deviation of DNA restriction fragments from the 3.2-Mbp mark during electrophoresis suggests occurrence of breakage and failed reconstruction in this segment of chromosome 21; induction of mutations can be inferred from the change in the size of the restriction fragments. The remaining 22 chromosomes are not considered. This method may not be sensitive enough to detect small base changes.
Cell cycle can influence the repair pathway of DSBs and, thus, the risk of incorrect rejoining of broken ends. In G1 phase, NHEJ may be favoured, while in S, G2, or M phase, both HR and NHEJ have been observed to be active in repair (Mao et al., 2008b).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
DNA strand breaks and subsequent mutations can occur in any eukaryotic and prokaryotic cell. Any DNA strand break has potential to cause alterations in DNA sequence (e.g., deletions and insertions), whether it is due to insufficient or faulty repair.
Bunting, S. & A. Nussenzweig (2013), "End-joining, Translocations and Cancer", Nat Rev Cancer, 13:443-454.
Byrne, M. et al. (2014), "Mechanisms of oncogenic chromosomal translocations", Ann. N.Y. Acad. Sci., 1310:89-97.
Dikomey, E. & I. Brammer (2000), "Relationship between cellular radiosensitivity and non-repaired double-strand breaks studied for different growth states, dose rates and plating conditions in a normal human fibroblast line.", Int. J. Radiat. Biol., 76:773-781.
Dwivedi, G. & J.E. Haber (2018), "Assaying Mutations Associated With Gene Conversion Repair of a Double-Strand Break", Methods Enzymiol., 601:145-160.
Hicks, W. & J.E. Haber (2010), "Increased Mutagenesis and Unique Mutation Signature Associated with Mitotic Gene Conversion", Nat. Rev. Cancer, 329:82-84.
Kuhne, M., K. Rothkamm & M. Lobrich (2000), "No dose-dependence of DNA double-strand break misrejoining following a -particle irradiation.", Int. J. Radiat. Biol. 76(7):891-900
Kuhne, M., G. Urban & M. Lo, (2005), "DNA Double-Strand Break Misrejoining after Exposure of Primary Human Fibroblasts to C K Characteristic X Rays, 29 kVp X Rays and Co g-Rays.", Radiation Research. 164(5):669-676. doi:10.1667/RR3461.1.
Lobrich, M. et al. (2000), "Joining of Correct and Incorrect DNA Double-Strand Break Ends in Normal Human and Ataxia Telangiectasia Fibroblasts.", 68(July 1999):59–68. doi: 10.1002/(SICI)1098-2264(200001)27:1<59::AID-GCC8>3.0.CO;2-9.
Mao, Z. et al. (2008a), "Comparison of nonhomologous end joining and homologous recombination in human cells.", DNA Repair, 7:1765-1771.
Mao, Z. et al. (2008b), "DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells.", Cell Cycle, 7:2902-2906.
McMahon, S.J. et al. (2016), "Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.", Nat. Publ. Gr.(April):1–14. doi:10.1038/srep33290.
Platel, A. et al. (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.
Polo, S. & S. Jackson (2011), "Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.", Genes Dev., 25:409-433.
Ptacek, O. et al. (2001), "Induction and repair of DNA damage as measured by the Comet assay and the yield of somatic mutations in gamma-irradiated tobacco seedlings.", Mutat. Res., 491:17-23.
Rodgers, K. & M. McVey (2016), "Error-prone repair of DNA double-strand breaks.", J. Cell. Physiol., 231:15-24.
Rothkamm, K. & M. Lobrich (2003), "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.", PNAS, 100(9):5057-62. doi:10.1073/pnas.0830918100.
Rydberg, B. 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.", Radiat. Res. 163(5):526–534. doi:10.1667/RR3346.
Spassova, M. et al. (2013), "Dose-Response Analysis of Bromate-Induced DNA Damage andMutagenicity Is Consistent With Low-Dose Linear,Nonthreshold Processes", Environ. Mol. Mutagen., 54:19-35.