Increase, Oxidative DNA damage leads to Increase, DNA strand breaks

The repair of oxidative DNA lesions produced by exposure to reactive oxygen species (ROS) involves excision repair, where damaged base is removed by glycosylases, a strand break is generated 5’ to the apurinic/apyrimidinic (AP) site by lyases and endonucleases, and finally, a new strand is synthesized across the break. Although these strand breaks are mostly transient under normal conditions, elevated levels of oxidative DNA lesions can increase the early AP lyase activities generating a higher number of SSBs that can be more persistent (Yang et al., 2004; Yang et al., 2006). These SSBs can exacerbate the DNA damage by interfering with the replication fork causing it to collapse, and ultimately becoming double strand breaks (DSBs).      

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022.  Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

A limited number of studies explored the quantitative correlation between oxidative DNA lesions and DNA strand breaks. There are computational models availabe that describe this relationship. Spassova et al. (2015) developed a simulated kinetic model of KBrO₃-induced oxidative DNA damage based on Michaelis-Menten enzyme kinetics to study the effect of BER on the shape of the dose-response curve of 8-oxo-dG lesions and strand breaks (Spassova et al., 2015).

• Both time and concentration dependence of the responses were explored.
• The time course simulation of a sustained exposure at various concentrations produced a sharp increase in 8-oxo-dG immediately following exposure.
  • The authors attributed this accumulation to lagged, inefficient repair.
• This increase was later followed by a steep decrease in 8-oxo-dG lesions, accompanied by a linear increase in SSBs.
  • The repair of adducts by BER, both successful and failed, are responsible for the decrease of 8-oxo-dG; the SSBs are generated as a result of repair failure. 
• Moreover, the concentration-response model of 8-oxo-dG showed a thresholded curve, where no DNA damage was observed at low concentrations due to effective repair up to a certain concentration of KBrO₃ indicating insufficient repair at the inflection point.

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