Non-targeted effects and DNA: vulnerabilities at the interface

Objectives This paper aims to explore areas of radiobiological research where DNA-targeted effects interface with non-DNA-targeted effects (NTEs). While target theory established in the 1930s claims that DNA was a primary target for radiation-induced cellular damage, non-targeted effects, although known from 1905, were largely ignored. In this narrative review, the data will be examined showing that DNA damage can not only be directly caused by radiation but also be induced in non-hit cells due to signaling factors. Similarly, DNA repair systems can be induced in situations where no radiation was delivered to the system. The implications of these data for radiotherapy, especially new modalities, and low-dose radiation protection are discussed. Conclusions The data clearly show that out-of-field and abscopal effects as well as inter-individual signaling occur and induce a variety of responses in non-targeted cells. In many cases, these mechanisms appear to be system-level effects coordinating responses to DNA damage at a level higher and more complex than the individual cell/tissue that receives a direct radiation exposure. This implies that NTEs, although often measured using endpoints seen as “bad” at the level of the individual targeted cell, are actually protective, and counteract vulnerabilities in cellular-level DNA repair systems. This has implications for the design of novel therapies for cancer and may also help in understanding mechanisms of low-dose radiation carcinogenesis.