Boreham D R, Mitchel R E
Atomic Energy of Canada Limited, Radiation Biology Branch, Chalk River, Ontario, Canada.
Radiat Res. 1991 Oct;128(1):19-28.
DNA recombinational repair, and an increase in its capacity induced by DNA damage, is believed to be the major mechanism that confers resistance to killing by ionizing radiation in yeast. We have examined the nature of the DNA lesions generated by ionizing radiation that induce this mechanism, using two different end points: resistance to cell killing and ability of the error-free recombinational repair system to compete for other DNA lesions and thereby suppress chemical mutation. Under the various conditions examined in this study, the "maximum" inducible radiation resistance was increased approximately 1.5- to 3-fold and suppression of mutation about 10-fold. DNA lesions produced by low-LET gamma rays at doses greater than about 20 Gy given in oxygen were shown to be more efficient, per unit dose, at inducing radioresistance to killing than were lesions produced by neutrons (high-LET radiation). This suggests that DNA single-strand breaks are more important lesions in the induction of radioresistance than DNA double-strand breaks. Oxygen-modified lesions produced by gamma rays (low-LET radiation) were particularly efficient as induction signals. DNA damage due to hydroxyl radicals (OH.) derived from the radiolytic decomposition of H2O produced lesions that strongly induced this DNA repair mechanism. Similarly, OH. derived from aqueous electrons (e-aq) in the presence of N2O also efficiently induced the response. Cells induced to radioresistance to killing with high-LET radiation did not suppress N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-generated mutations as well as cells induced with low-LET radiation, supporting the conclusion that the type of DNA damage produced by low-LET radiation is a better inducer of recombinational repair. Surprisingly, however, cells induced with gamma radiation in the presence of N2O that became radioresistant to killing were unable to suppress MNNG mutations. This result indicates that OH. generated via e-aq (in N2O) may produce unusual DNA lesions which retard normal repair and render the system unavailable to compete for MNNG-generated lesions. We suggest that the repairability of these unique lesions is restricted by either their chemical nature or topological accessibility. Attempted repair of these lesions has lethal consequences and accounts for N2O radiosensitization of repair-competent but not incompetent cells. We conclude that induction of radioresistance in yeast by ionizing radiation responds variably to different DNA lesions, and these affect the availability of the induced recombinational repair system to deal with subsequent damage.
DNA重组修复以及由DNA损伤诱导产生的修复能力增强，被认为是酵母对电离辐射杀伤产生抗性的主要机制。我们使用了两个不同的终点来研究诱导这种机制的电离辐射所产生的DNA损伤的性质：细胞杀伤抗性以及无差错重组修复系统竞争其他DNA损伤从而抑制化学诱变的能力。在本研究中所检测的各种条件下，“最大”诱导辐射抗性增加了约1.5至3倍，突变抑制约为10倍。在有氧条件下，当低传能线密度（LET）的γ射线剂量大于约20 Gy时产生的DNA损伤，每单位剂量在诱导抗辐射杀伤方面比中子（高LET辐射）产生的损伤更有效。这表明DNA单链断裂在诱导辐射抗性方面比DNA双链断裂更重要。γ射线（低LET辐射）产生的氧修饰损伤作为诱导信号特别有效。由H2O的辐射分解产生的羟基自由基（OH·）导致的DNA损伤能强烈诱导这种DNA修复机制。同样，在N2O存在下由水合电子（e-aq）产生的OH·也能有效诱导这种反应。用高LET辐射诱导产生抗辐射杀伤能力的细胞，在抑制N-甲基-N'-硝基-N-亚硝基胍（MNNG）产生的突变方面不如用低LET辐射诱导的细胞，这支持了低LET辐射产生的DNA损伤类型是重组修复更好诱导剂的结论。然而，令人惊讶的是，在N2O存在下用γ辐射诱导产生抗辐射杀伤能力的细胞无法抑制MNNG突变。这一结果表明，通过e-aq（在N2O中）产生的OH·可能产生异常的DNA损伤，阻碍正常修复并使该系统无法竞争MNNG产生的损伤。我们认为这些独特损伤的可修复性受到其化学性质或拓扑可及性的限制。尝试修复这些损伤会产生致命后果，并解释了N2O对具有修复能力而非无修复能力细胞的放射增敏作用。我们得出结论，电离辐射在酵母中诱导的辐射抗性对不同的DNA损伤反应各异，并且这些损伤会影响诱导的重组修复系统处理后续损伤的可用性。
