The role of the DNA damage response mechanisms after low-dose radiation exposure and a consideration of potentially sensitive individuals.
Here I consider whether radiation-sensitive individuals might exist in the population and the potential impact of low-dose/dose-rate radiation exposure. Radiation induces DNA double-strand breaks (DSBs), which cause lethality if they are unrepaired and enhance genomic instability if they are misrepaired. DNA damage response (DDR) mechanisms play a vital role in protecting cells from the harmful effects of DSB formation. The DDR encompasses DSB repair pathways, of which DNA nonhomologous end joining is the most significant, and a signal transduction process involving ATM. Patients defective in DDR proteins have been described, and some have shown clinical radiosensitivity. However, such patients are rare and belong to defined syndromes. The critical question is whether heterozygosity or mild defects in DDR proteins confer low-dose radiosensitivity. While it is unlikely that low-dose radiation will dramatically enhance cell killing in such patients, it is possible that there could be an impact on stem cell turnover, leading to stem cell depletion with age. More importantly, it is likely that such patients could have increased misrepair of radiation damage and hence an elevated risk of radiation-induced carcinogenesis. Evidence in support of this and the potentially important genes in this context are discussed.
Jeggo
Penny
P
Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom BN1 9RQ. p.a.jeggo@sussex.ac.uk
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011836:Radiation Tolerance; D025521:Tumor Suppressor Proteins / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D011088:DNA Ligases; D000072481:DNA Ligase ATP