Relationship: 164



N/A, Inadequate DNA repair leads to Increase, Mutations

Upstream event


N/A, Inadequate DNA repair

Downstream event


Increase, Mutations

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations adjacent High Moderate
Alkylation of DNA leading to cancer 2 adjacent High Moderate
Alkylation of DNA leading to cancer 1 non-adjacent High Moderate
Oxidative DNA damage leading to chromosomal aberrations and mutations adjacent High Low
Direct deposition of ionizing energy leading to lung cancer adjacent Moderate Moderate

Taxonomic Applicability


Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability


Sex Evidence
Unspecific High

Life Stage Applicability


Term Evidence
All life stages High

Key Event Relationship Description


Insufficient repair results in the retention of damaged DNA that is then used as a template during DNA replication. During replication of damaged DNA, incorrect nucleotides may be inserted, and upon replication these become ‘fixed’ in the cell. Further replication propagates the mutation to additional cells.

For example, it is well established that replication of alkylated DNA can cause insertion of an incorrect base in the DNA duplex (i.e., mutation). Replication of non-repaired O4 thymine alkylation leads primarily to A:T→G:C transitions. Retained O6 guanine alkylation causes primarily G:C→A:T transitions.

For repairing DNA double strand breaks (DSBs), non-homologous end joining (NHEJ) is one of the repair mechanisms used in human somatic cells (Petrini et al., 1997; Mao et al., 2008). However, this mechanism is error-prone and may create mutations during the process of DNA repair (Little, 2000). NHEJ is considered error-prone because it does not use a homologous template to repair the DSB. The NHEJ mechanism involves many proteins that work together to bridge the DSB gap by overlapping single-strand termini that are usually less than 10 nucleotides long (Anderson, 1993; Getts & Stamato, 1994; Rathmell & Chu, 1994). Inherent in this process is the introduction of errors that may result in mutations such as insertions, deletions, inversions, or translocations.

Evidence Supporting this KER


Biological Plausibility


If DNA repair is able to correctly and efficiently repair DNA lesions introduced by a genotoxic stressor, then no increase in mutation frequency will occur.

For example, for alkylated DNA, efficient removal by AGT will result in no increases in mutation frequency. However, above a certain dose AGT becomes saturated and is no longer able to efficiently remove the alkyl adducts. Replication of O-alkyl adducts leads to mutation. The evidence demonstrating that replication of unrepaired O-alkylated DNA causes mutations is extensive in somatic cells and has been reviewed (Basu and Essigmann 1990; Shrivastav et al. 2010); specific examples are given below.

It is important to note that not all DNA lesions will cause mutations. It is well documented that many are bypassed error-free. For example, N-alkyl adducts can quite readily be bypassed error-free with no increase in mutations (Philippin et al., 2014).

Inadequate repair of DSB

Collective data from tumors and tumor cell lines has emerged that suggests that DNA repair mechanisms may be error-prone (reviewed in Sishc et al., 2017) (Sishc & Davis, 2017).  NHEJ, the most common pathway used to repair DSBs, has been described as error-prone. The error-prone nature of NHEJ, however, is thought to be dependent on the structure of the DSB ends being repaired, and not necessarily dependent on the NHEJ mechanism itself (Bétermier et al., 2014). Usually when perfectly cohesive ends are formed as a result of a DSB event, ligase 4 (LIG4) will have limited end processing to perform, thereby keeping ligation errors to a minimum (Waters et al., 2014). When the ends are difficult to ligate, however, the resulting repair may not be completed properly; this often leads to point mutations and other chromosomal rearrangements. It has been shown that approximately 25 - 50% of DSBs are misrejoined after exposure to ionizing radiation (Löbrich et al., 1998; Kuhne et al., 2000; Lobrich et al., 2000). Defective repair mechanisms can increase sensitivity to agents that induce DSBs and lead eventually to genomic instability (reviewed in Sishc et al., (2017)).

Activation of mutagenic DNA repair pathways to withstand cellular or replication stress either from endogenous or exogenous sources can promote cellular viability, albeit at a cost of increased genome instability and mutagenesis (Fitzgerald et al., 2017). These salvage DNA repair pathways including, Break-induced Replication (BIR) and Microhomology-mediated Break-induced Replication (MMBIR). BIR repairs one-ended DSBs and has been extensively studied in yeast as well as in mammalian systems. BIR and MMBIR are linked with heightened levels of mutagenesis, chromosomal rearrangements and ensuing genome instability (Deem et al., 2011; Sakofsky et al., 2015; Saini et al., 2017; Kramara et al., 2018). In mammalian genomes BIR-like synthesis has been proposed to be involved in late stage Mitotic DNA Synthesis (MiDAS) that predominantly occurs at so-called Common Fragile Sites (CFSs) and maintains telomere length under s conditions of replication stress that serve to promote cell viability (Minocherhomji et al., 2015; Bhowmick et al., 2016; Dilley et al., 2016).       

Empirical Evidence



Evidence in somatic cells

Empirical evidence to support this KER is primarily from studies in which synthetic oligonucleotides containing well-characterized DNA lesions were genetically engineered in viral or plasmid genomes and subsequently introduced into bacterial or mammalian cells. Mutagenicity of each lesion is ascertained by sequencing, confirming that replication of alkylated DNA (i.e., unrepaired DNA) causes mutations in addition to revealing the important DNA repair pathways and polymerases involved in the process. For example, plasmids containing O6-methyl or O6-ethylguanine were introduced into AGT deficient or normal Chinese hamster ovary cells (Ellison et al. 1989). Following replication, an increase in mutant fraction to 19% for O6-methylguanine and 11% for O6-ethylguanine adducts was observed in AGT deficient cells versus undetectable levels for control plasmids. The relationship between input of alkylated DNA versus recovered mutant fractions revealed that a large proportion of alkyl adducts were converted to mutations in the AGT deficient cells (relationship slightly sublinear, with more adducts than mutations). The primary mutation occurring was G:C-A:T transitions. The results indicate that replication of the adducted DNA caused mutations and that this was more prevalent with reduced repair capacity. The number of mutations measured is less than the unrepaired alkyl adducts transfected into cells, supporting that insufficient repair occurs prior to mutation. Moreover, the alkyl adducts occur prior to mutation formation, demonstrating temporal concordance.

Various studies in cultured cells and microorganisms have shown that the expression of AGT/MGMT (repair machinery – i.e., decrease in KE1) greatly reduces the incidence of mutations caused by exposure to methylating agents such as MNU and MNNG (reviewed in Kaina et al. 2007; Pegg 2011). Thomas et al. (2013) used O6-benzylguanine to specifically inhibit MGMT activity in AHH-1 cells. Inhibition was carried out for one hour prior to exposure to MNU, a potent alkylating agent. Inactivation of MGMT resulted in increased MNU-induced HPRT (hypoxanthine-guanine phosphoribosyltransferase) mutagenesis and shifted the concentrations at which induced mutations occurred to the left on the dose axis (10 fold reduction of the lowest observed genotoxic effect level from 0.01 to 0.001 µg/ml). The ratio of mutants recovered in DNA repair deficient cells was 3-5 fold higher than repair competent cells at concentrations below 0.01 µg/ml, but was approximately equal at higher concentrations, indicating that repair operated effectively to a certain concentration. Only at this concentration (above 0.01 µg/ml when repair machinery is overwhelmed and repair becomes deficient) do the induced mutations in the repair competent cells approach those of repair deficient. Thus, induced mutation frequencies in wild type cells are suppressed until repair is overwhelmed for this alkylating agent. The mutations prevented by MGMT are predominantly G:C-A:T transitions caused by O6-methylguanine.

Evidence in germ cells

That saturation of repair leads to mutation in spermatogonial cells is supported by work using the OECD TG488 rodent mutation reporter assay in sperm. A sub-linear dose-response was found using the lacZ MutaMouse assay in sperm exposed as spermatogonial stem cells, though the number of doses was limited (van Delft and Baan 1995). This is indirect evidence that repair occurs efficiently at low doses and that saturation of repair causes mutations at high doses. Lack of additional data motivated a dose-response study using the MutaMouse model following both acute and sub-chronic ENU exposure by oral gavage (O’Brien et al. 2015). The results indicate a linear dose-response for single acute exposures, but a sub-linear dose-response occurs for lower dose sub-chronic (28 day) exposures, during which mutation was only observed to occur at the highest dose. This is consistent with the expected pattern for dose-response based on the hypothesized AOP. Thus, this sub-linear curve for mutation at low doses following sub-chronic ENU exposure suggests that DNA repair in spermatogonia is effective in preventing mutations until the process becomes overwhelmed at higher doses.

Mutation spectrum: Following exposure to alkylating agents, the most mutagenic adducts to DNA in pre-meiotic male germ cells include O6-ethylguanine, O4-ethylthymine and O2-ethylthymine (Beranek 1990; Shelby and Tindall 1997). Studies on sperm samples collected post-ENU exposure in transgenic rodents have shown that 70% of the observed mutations are at A:T sites (Douglas et al. 1995). The mutations observed at G:C base pairs are almost exclusively G:C-A:T transitions, presumably resulting from O6-ethylguanine. It is proposed that the prevalence of mutations at A:T basepairs is the result of efficient removal of O6-alkylguanine by AGT in spermatogonia, which is consistent with observation in human somatic cells (Bronstein et al. 1991; Bronstein et al. 1992). This results in the majority of O6-ethylguanine adducts being removed, leaving O4- and O2-ethylthymine lesions to mispair during replication. Thus, lack of repair predominantly at thymines and guanines at increasing doses leads to mutations in these nucleotides, consistent with the concordance expected between diminished repair capabilities at these adducts and mutation induction (i.e., concordance relates to seeing these patterns across multiple studies, species and across the data in germ cells and offspring).


Inadequate repair of oxidative DNA lesions: In vitro studies

  • AS52 Chinese hamster ovary cells (wild type and OGG1-overexpressing) were exposed to kJ/m2 UVA radiation (Dahle et al., 2008).
    • Mutations in the gpt gene were quantified in both wild type and OGG1+ cells by sequencing after 13-15 days following 400 kJ/m2 UVA irradiation
      • G:C-A:T mutations in UVA-irradiated OGG1+ cells were completely eliminated
      • G:C-A:T mutation frequency in wild type cells increased from 1.8 mutants/million cells to 3.8 mutants/million cells following irradiation – indicating incorrect repair or lack of repair of accumulated 8-oxo-dG
      • Elevated levels of OGG1 was able to prevent G:C-A:T mutations, while the OGG1 levels in wild type cells was insufficient, leading to an increase in mutants (demonstrates inadequate repair leading to mutations)
  • Xeroderma pigmentosum complementation group A (XPA) knockout (KO) and wild type TSCER122 human lymphoblastoid cells were transfected with TK gene-containing vectors with no adduct, a single 8-oxo-dG, or two 8-oxo-dG adducts in tandem (Sassa et al., 2015).
    • XPA is a key protein in nucleotide excision repair (NER) that acts as a scaffold in the assembly the repair complex.
    • Mutation frequency was determined by the number of TK-revertant colonies
    • Control vector induced a mutation frequency of 1.3% in both WT and XPA KO
    • Two 8-oxo-dG in tandem on the transcribed strand were most mutagenic in XPA KO, inducing 12% mutant frequency compared to 7% in WT
    • For both XPA KO and WT, G:C-A:T transversion due to 8-oxo-dG was the most predominant point mutation in the mutants 
    • The lack of a key factor in NER leading to increased 8-oxo-dG-induced transversions demonstrates insufficient repair leading to increase in mutations 


Inadequate repair of oxidative DNA lesions: In vivo studies in mice

  • Spontaneous mutation frequencies in the liver of Ogg1-deficient (-/-) Big Blue mice was measured at 10 weeks of age (Klungland et al., 1999).
    • Mutation frequencies were 2- to 3-fold higher in the Ogg1-/- mice than in wild type
    • Of the 16 base substitutions detected in Ogg1 -/- mutant plaques analyzed by sequencing, 10 indicated G:C-A:T transversions consistent with the known spectrum of mutation
    • The results support that insufficient repair of oxidized bases leads to mutation.
  • Ogg1 knockout (Ogg1-/-) in C57BL/6J mice resulted in 4.2-fold and 12-fold increases in the amount of 8-oxo-dG in the liver compared to wild type at 9 and 14 weeks of age, respectively (Minowa et al., 2000).
    • In these mice, there was an average of 2.3-fold increase in mutation frequencies in the liver (measured between 16-20 weeks)
      • 57% of the observed base substitutions were G:C-A:T transversions, while 35% in wild type mice corresponded to this transversion.
      • Approximately 70% of the increase in mutation frequency was due to G to T transversions.
    • Concordantly, KBrO3 treatment resulted in a 2.9-fold increase in mutation frequency in the kidney of Ogg1 -/- mice compared to KBrO3-treated wild type (Arai et al., 2002).
      • G:C-A:T transversions made up 50% of the base substitutions in the Ogg1-/- mice.
    • Heterozygous Ogg1 mutants (Ogg1+/-) retained the original repair capacity, where no increase in 8-oxo-dG lesions was observed in the liver at 9 and 14 weeks (Minowa et al., 2000).
      • This observation was consistent even after KBrO3 treatment of the mice (Arai et al., 2002).
    • From these results, we can infer that OGG1 proteins are present in excess and that one functional copy of the gene is sufficient in addressing endogenous and, to a certain degree, chemical-induced oxidative DNA lesions.

Inadequate Repair of DSB

Empirical data obtained for this KER moderately supports the idea that inadequate DNA repair increases the frequency of mutations. The evidence presented below related to the inadequate repair of DSBs is summarized in table 5, here (click link). The review article by Sishc & Davis (2017) provides an overview of NHEJ mechanisms with a focus on the inherently error-prone nature of DSB repair mechanisms, particularly when core proteins of NHEJ are knocked-out. Another review also provides an overview of DSB induction, the repair process and how mutations may result, as well as the biological relevance of misrepaired or non-repaired DNA damage (Sage & Shikazono, 2017).

Dose and Incidence Concordance

There is evidence in the literature suggesting a dose/incidence concordance between inadequate DNA repair and increases in mutation frequencies. Evidence presented below related to the dose-response of mutation frequencies is summarized in table 2, here (click link). In response to increasing doses from a radiation stressor, dose-dependent increases in both measures of inadequate DNA repair and mutation frequency have been found. In an analysis that amalgamated results from several different studies conducted using in vitro cell-lines, the rate of DSB misrepair was revealed to increase in a dose-dependent fashion from 0 - 80 Gy, with the mutation rate also similarly increasing from 0 - 6 Gy (Mcmahon et al., 2016). Additionally, using a plant model, it was shown that increasing radiation dose from 0 - 10 Gy resulted in increased DNA damage as a consequence of inadequate repair.  Mutations were observed 2 - 3 weeks post-irradiation (Ptácek et al., 2001). Moreover, increases in mutation densities were found in specific genomic regions of cancer samples (namely promoter DNAse I-hypersensitive sites (DHS) and 100 bp upstream of transcription start sites (TSS)) that were also found to have decreased DNA repair rates attributable to inadequate nucleotide excision repair (NER) (Perera et al., 2016).

Interestingly, mutation rates have been shown to increase as the required DNA repair becomes more complex. Upon completion of DSB repair in response to radiation and treatment with restriction enzymes, more mutations were found in cases where the ends were non-complementary and thus required more complex DNA repair (1 - 4% error-free) relative to cases where ends were complementary (34 - 38% error-free) (Smith et al., 2001).

Temporal Concordance

There is evidence in the literature suggesting a time concordance between the initiation of DNA repair and the occurrence of mutations. For simple ligation events, mutations were not evident until 12 - 24 hours, whereas DSB repair was evident at 6 -12 hours. For complex ligation events, however, mutations and DSB repair were both evident at 12 - 24 hours. As the relative percent of DNA repair increased over time, the corresponding percent of error-free rejoining decreased over time in both ligation cases, suggesting that overall DNA repair fidelity decreases with time ((Smith et al., 2001).


There is evidence from knock-out/knock-down studies suggesting that there is a strong relationship between the adequacy of DNA repair and mutation frequency.  In all examined cases, deficiencies in proteins involved in DNA repair resulted in altered mutation frequencies relative to wild-type cases. There were significant decreases in the frequency and accuracy of DNA repair in cell lines deficient in LIG4 (Smith et al., 2003) and Ku80 (Feldmann et al., 2000); rescue experiments performed with these two cell lines further confirmed that inadequate DNA repair was the cause of the observed decreases in repair frequency  and accuracy (Feldmann et al., 2000; Smith et al., 2003). In primary Nibrin-deficient mouse fibroblasts, there was increased spontaneous DNA damage relative to wild-type controls, suggestive of inadequate DNA repair. Using the corresponding Nibrin-deficient and wild-type mice, in vivo mutation frequencies were also found to be elevated in the Nibrin-deficient animals (Wessendorf et al., 2014). Furthermore, mutation densities were differentially affected in specific genomic regions in cancer patients depending on their XPC status. Specifically, mutation frequencies were increased in XPC-wild-type patients at DHS promoters and 100 bp upstream of TSS relative to cancer patients lacking functional XPC (Perera et al., 2016) .  Lastly, in a study using WKT1 cells with less repair capacity, radiation exposure induced four times more mutations in these cells than in TK6 cell, which had a normal repair capacity (Amundson and Chen, 1996).

Uncertainties and Inconsistencies


Repair of alkylated DNA

There were no inconsistencies in the empirical data reviewed or in the literature relating to biological plausibility. Much of the support for this KER comes predominantly from data in somatic cells and in prokaryotic organisms. We note that all of the data in germ cells used in this KER are produced exclusively from ENU exposure. Data on other chemicals are required. We consider the overall weight of evidence of this KER to be strong because of the obvious biological plausibility of the KER, and documented temporal association and incidence concordance based on studies over-expressing and repressing DNA repair in somatic cells.

Repair of oxidative lesions

  • Thresholded concentration-response curve of mutation frequency was observed in AHH-1 human lymphoblastoid cells after treatment with pro-oxidants (H2O2 and  KBrO2) known to cause oxidative DNA damage (Seager et al., 2012), suggesting that cells are able to tolerate low levels of DNA damage using basal repair. However, increase in 8-oxo-dG lesions and up-regulation of DNA repair proteins were not observed under the same experimental condition.
  • Mutagenicity of oxidative DNA lesions other than 8-oxo-dG, such as FaPydG and thymidine glycol, has not been as extensively studied and there are mixed results regarding the mutagenic outcome of these lesions.


  • Mutation induction is stochastic, spontaneous, and dependent on the cell type as well as the individual’s capability to repair efficiently (NRC, 1990; Pouget & Mather, 2001).

Quantitative Understanding of the Linkage


Thresholds for mutagenicity indicate that the response at low doses is modulated by the DNA repair machinery, which is effectively able to remove alkylated DNA at low doses [Gocke and Muller 2009; Lutz and Lutz 2009; Pozniak et al. 2009]. Kinetics of DNA repair saturation in somatic cells is described in Muller et al. [Muller et al. 2009].

For O-methyl adducts, once the primary repair process is saturated, in vitro data suggest that misreplication occurs almost every time a polymerase encounters a methylated guanine [Ellison et al. 1989; Singer et al. 1989]; however, it should be noted that this process can be modulated by flanking sequence. This conversion of adducts to mutations also appears to be reduced substantially in vivo [Ellison et al. 1989]. The probability of mutation will also depend on the type of adduct (e.g., O-alkyl adducts are more mutagenic than N-alkyl adducts; larger alkyl groups are generally more mutagenic, etc.). Overall, a substantive number of factors must be considered in developing a quantitative model.

Inadequate repair of oxidative lesions

The relationship between the quantity/activity of repair enzymes such as OGG1 in the cell and the quantity of oxidative lesions need to be better understood to define a threshold on the quantity of oxidative lesions exceeding basal repair capacity. Moreover, the proportion of oxidative lesions formed that lead to mutation versus strand breaks is not clearly understood.

Mutations resulting from oxidative DNA damage can occur via replicative polymerases and translesion synthesis (TLS) polymerases during replication, and during attempted repair. However, an in vitro study on TLS in yeast has shown that bypass of 8-oxo-dG by TLS polymerases during replication is approximately 94-95% accurate. Therefore, the mutagenicity of 8-oxo-dG and other oxidative lesions may depend on their abundance, not on a single lesion (Rodriguez et al., 2013). Applicability of this observation in mammalian cells needs further investigation. Information on the accuracy of 8-oxo-dG bypass in mammalian cells is limited.      

The most notable example of mutation arising from inadequate repair of DNA oxidation is G to T transversion due to 8-oxo-dG lesions. Previous studies have demonstrated higher mutation frequency of this lesion compared to other oxidative lesions; for example, Tan et al. (1999) compared the mutation rate of 8-oxo-dG and 8-oxo-dA in COS-7 monkey kidney cells and reported that under similar conditions, 8-oxo-dG was observed to be four times more likely to cause base substitution (Tan et al., 1999). 

Inadequate Repair of DSB

Quantitative understanding of this linkage is derived from the studies that examined DSB misrepair rates or mutation rates in response to a radiation stressor.  In general, combining results from these studies suggests that increased mutations can be predicted when DNA repair is inadequate. At a radiation dose of 10 Gy, the rate of DSB misrepair was found to be approximately 10 - 15% (Lobrich et al., 2000); this rate increased to 50 - 60% at a radiation exposure of 80 Gy (Kuhne et al., 2000; Lobrich et al., 2000; McMahon et al., 2016). For mutation rates in response to radiation across a variety of models and radiation doses, please refer to the example table below.

Reference Summary
Matuo et al., 2018 Yeast cells (saccharomyces cerevisiae) exposed to high LET cardbon ions (25 keV/um) and low LET carbon ions (13 keV/um) between 0-200 Gy induces a 24-fold increase overbaseline of mutations (high LET) and 11-fold increase over baseline mutations (low LET).
Nagashima et al., 2018 Hamster cells (GM06318-10) exposed to x-rays in the 0-1 Gy. Response of 19.0 ± 6.1 mutants per 109 survivors.
Albertini et al., 1997 T-lymphcytes isolated from human peripheral blood exposed to low LET gamma-rays (0.5-5 Gy) and high LET radon gas (0-1 Gy). Response of 7.0x10-6 mutants/Gy (Gamma-rays 0-2 Gy), 54x10-6 mutants/Gy (Gamma-rays 2-4 Gy) and 63x10-6 mutants/Gy (0-1 Gy).
Dubrova et al., 2002 Observation of paternal ESTR mutation rates in CBAH mice following exposure to acute low LET X-rays (0-1 Gy), chronic low LET gamma-rays (0-1 Gy) and chronic high LET neutrons (0-0.5 Gy). Modelled response of y = mx + C, values of (m,C): X-rays: (0.338, 0.111), Gamma-rays: (0.373±0.082, 0.110), Neutrons: (1.135±0.202, 0.136).
McMahon et al., 2016 Study of HPRT gene in Chinese hamster cells following exposure to radiation of 1-6 Gy. Observation of 0.2 mutations in HPRT gene per 104 cells and 0.1 point mutations per 104 cells (1 Gy). At 6 Gy, observation of 1.5 mutations in the HPRT gene per 104 cells and 0.4 point mutations per 104 cells.


Response-response Relationship


Inadequate Repair of DSB

There is evidence of a response-response relationship between inadequate DNA repair and increased frequency of mutations. When exposed to a radiation stressor, there was a positive relationship between the radiation dose and the DSB misrepair rate, and between the mutation rate and the radiation dose (Mcmahon et al., 2016). Similarly, there was a negative correlation found between NER and the mutation densities at specific genomic regions in cancer patients. Specifically, inadequate NER resulted in more mutations in the promoter DHS and the TSS, but normal NER at DHS flanking regions resulted in fewer mutations (Perera et al., 2016).



Inadequate Repair of DSB

Two studies were used to provide data regarding the time scale of DNA repair and the appearance of mutations. In a study using plants, DNA damage was evident immediately following radiation with 30 Gy of radiation; 50% of repairs were complete by 51.7 minutes, 80% by 4 hours, and repair was completed by 24 hours post-irradiation. Although no mutational analysis was performed during the period of repair, irradiated plants were found to have increased mutations when they were examined 2 - 3 weeks later (Ptácek et al., 2001). Both DNA repair and mutation frequency were examined at the same time in a study comparing simple and complex ligation of linearized plasmids. In this study, repaired plasmids were first detected between 6 - 12 hours for simple ligation events and between 12 - 24 hours for more complex ligation events; this first period was when the most error-free rejoining occurred in both cases. After this initial period of repair until its completion at 48 hr, repair became increasingly more erroneous such that mutations were found in more than half of the repaired plasmids at 48 hr regardless of the type of required ligation (Smith et al., 2001).

Known modulating factors


Not identified.

Known Feedforward/Feedback loops influencing this KER


Not identified.

Domain of Applicability


The domain of applicability is multicellular eukaryotes (Lieber, 2008; Hartlerode & Scully, 2009), plants (Gorbunova, 1997; Puchta, 2005), certain strains of bacteria such as Mycobacteria, PseudomonasBacillus and Agrobacterium (Shuman & Glickman, 2007), and yeast (Wilson & Lieber, 1999).

All organisms, from prokaryotes to eukaryotes, have DNA repair systems. Indeed, much of the empirical evidence on the fundamental principles described in this KER are derived from prokaryotic models. DNA adducts can occur in any cell type, and may or may not be repaired, leading to mutation. While there are differences among DNA repair systems across eukaryotic taxa, all species develop mutations following excessive burdens of DNA lesions like DNA adducts. Theoretically, any sexually reproducing organism (i.e., producing gametes) can also acquire DNA lesions that may or may not be repaired, leading to mutations in gametes.



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