The Significance of the Response: Beyond the Mechanics of DNA Damage and Repair-Physiological, Genetic, and Systemic Aspects of Radiosensitivity in Higher Organisms.

Classical radiation biology as we understand it clearly identifies genomic DNA as the primary target of ionizing radiation. The evidence appears rock-solid: ionizing radiation typically induces DSBs with a yield of ~30 per cell per Gy, and unrepaired DSBs are a very cytotoxic lesion. We know very well the kinetics of induction and repair of different types of DNA damage in different organisms and cell lines. And yet, higher organisms differ in their radiation sensitivity-humans can be unpredictably radiosensitive during radiotherapy; this can be due to genetic defects (e.g., ataxia telangiectasia (AT), Fanconi anemia, Nijmegen breakage syndrome (NBS), and the xeroderma pigmentosum spectrum, among others) but most often is unexplained. Among other mammals, goats () appear to be very radiosensitive (LD = 2.4 Gy), while Mongolian gerbils () are radioresistant and withstand quadruple that dose (LD = 10 Gy). Primary radiation lethality in mammals is due most often to hematopoietic insufficiency, which is, in the words of Dr. Theodor Fliedner, one of the pioneers of radiation hematology, "a disturbance in cellular kinetics". And yet, what makes one cell type, or one particular organism, more sensitive to ionizing radiation? The origins of radiosensitivity go above and beyond the empirical evidence and models of DNA damage and repair-as scientists, we must consider other phenomena: the radiation-induced bystander effect (RIBE), abscopal effects, and, of course, genomic instability and immunomodulation. It seems that radiosensitivity is not entirely determined by the mathematics of DNA damage and repair, and it is conceivable that radiation biology may benefit from an informed enquiry into physiology and organism-level signaling affecting radiation responses. The current article is a review of several key aspects of radiosensitivity beyond DNA damage induction and repair; it presents evidence supporting new potential venues of research for radiation biologists.