Risks from low dose/dose rate radiation: what an understanding of DNA damage response mechanisms can tell us.
The DNA damage response (DDR) mechanisms represent a vital line of defense against exogenous and endogenous DNA damage to enhance two distinct outcomes, survival and the maintenance of genomic stability. The latter is critical for cancer avoidance. DDR processes encompass repair pathways and signal transduction mechanisms that activate cell cycle checkpoint arrest and apoptosis. DNA double strand breaks (DSBs) represent important radiation-induced lesions. The major DSB repair pathways are DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) and ataxia telangiectasia mutated (ATM) activates the DSB signaling response. To evaluate the ability of these pathways to protect against low doses or dose rate radiation exposure, it is important to consider the fidelity of DSB repair and the sensitivity of checkpoint arrest and apoptosis. Radiation-induced DSBs are more complex than endogenously-induced DSBs, with the potential for multiple lesions to arise in close proximity. NHEJ, the major DSB repair pathway, cannot accurately reconstitute sequence information lost at DSBs. Both pathways have the potential to cause translocations by rejoining erroneous DNA ends. Thus, complete accuracy of repair cannot be guaranteed and the formation of translocations, which have the potential to initiate carcinogenesis, can arise. Additionally, the G2/M checkpoint has a defined sensitivity, allowing some chromosome breakage to occur. Thus, genomic rearrangements can potentially arise even if the G1/S checkpoint is efficient. The sensitivity of apoptosis is currently unclear but will likely differ between tissues. In summary, it is unlikely that the DDR mechanisms can fully protect cells from genomic rearrangements following exposure to low doses or dose rate radiation.
Jeggo
Penny A
PA
Genome Damage and Stability Centre, University of Sussex; Brighton BN1 9RQ, UK. p.a.jeggo@sussex.ac.uk
D000818:Animals; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D018499:Linear Energy Transfer; D011829:Radiation Dosage; D011995:Recombination, Genetic / Q000528:radiation effects; D012306:Risk; D015398:Signal Transduction / Q000528:radiation effects; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects