Inadequate DNA repair leads to Increase, Mutations

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.

Not identified.

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.

This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from in vivo adult mice and male human, and mice in vitro models. 

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 with DNA, 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.