低剂量电离辐射诱导免疫适应性反应的DNA修复机制
摘要
DNA修复是低剂量电离辐射诱导适应性反应的主要机制之一。辐射等因素主要引起DNA双链断裂(DSB),损伤的修复以非同源末端连接(NHEJ)为主,NHEJ修复相关基因有p53、PI3K家族成员(ATM、DNA-PKcs)和PARP-1等。
本实验采用分子生物学手段,在离体水平观察低剂量辐射诱导EL-4细胞凋亡及细胞周期进程的适应性反应,伴随其相关基因蛋白和mRNA水平的变化。同时,应用ATM和DNA-PK阻断剂渥曼青霉素,PARP-1阻断剂3-AB进一步证实上述基因在适应性反应中的作用。
实验表明,低剂量辐射可以在体外诱导EL-4细胞凋亡及细胞周期进程的适应性反应。在低剂量辐射诱导适应性反应中,p53表达减少,ATM和DNA-PKcs表达无明显变化,PARP-1表达增加;应用3-AB后未出现适应性反应。渥曼青霉素对适应性反应无影响,可能与渥曼青霉素作用机制有关,即其抑制ATM和DNA-PK,但不抑制p38MAPK及PKC,而后者可激活p53蛋白。
以上结果显示:p53和PARP-1基因均在适应性反应中起作用。其中,p53基因在适应性反应中起决定性作用,而ATM和DNA-PK无明显作用。表明DNA修复可能是低剂量电离辐射诱导适应性反应的主要机制。
Low dose radiation (LDR) could induce adaptive response, which has certain regularity. It has not been fully clear about the mechanism of adaptive response (AR) induced by LDR. Recent studies show that adaptive response might be mainly related with the improvement of DNA repair. At present, there’s some striking development in the study of DNA damage repair mechanism of adaptive response showed by consistent viewpoint that non-homologous end-joining (NHEJ) repair of DNA double strand break repair was the main factor in five ways of DNA damage repair to induce AR. p53 may play critical effects in this DNA repair way. It has not been very clear about the mechanism of p53, phosphatidylinositol 3-kinase (PI3K) families (ataxia-telangiectasia mutated gene, ATM; DNA-dependent protein kinase, DNA-PK) and poly-(ADP ribose) polymerase (PARP) in adaptive response, which were the main regulatory genes in NHEJ repair way. To explore further the DNA damage repair mechanism of LDR, the dose-, dose rate- and time-effects of adaptive response of apoptosis and cell cycle progression in EL-4 cells induced by low dose radiation were observed in the present experiment, and the mRNA and protein expressions of p53, ATM, DNA-PK catalytic subunit (DNA-PKcs) and PARP-1 gene were determined, at the same time, wortmannin which is the blocking agent of ATM and DNA-PK and 3-aminobenzamid (3-AB) which is PARP-1 blocking agent were used. There’s no related report in this study up to now around the world.
1 Dose-, dose rate- and time-effects of adaptive response of cell apoptosis and cell cycle progression induced by low dose radiation in EL-4 cells Lyphoma EL-4 cells were irradiated with inductive doses (doses of D1: 25, 50, 100 and 200 mGy; dose rate: 12.5 mGy/min; dose of D1: 75 mGy, dose rates: 6.25, 12.5, 25, 50, 100 and 200 mGy/min) and challenging doses (doses of D2: 0.5, 1.0, 1.5, 2.0 and 3.0 Gy, dose rate: 287 mGy/min), the intervals between D1 and D2 were 3, 6, 12, 24, 48 and 60 h, respectively. The cell apoptosis and cell cycle progression were measured with flow cytometer.
The results showed that when the doses of D1 were 25– 100 mGy (the dose rate: 12.5 mGy/min, the interval between D1 and D2: 6 h) or the dose of D1 was 75 mGy (the dose rates: 6.25– 50 mGy/min, the intervals between D1 and D2: 3 to 24 h), and the doses of D2 were 0.5– 3.0 Gy (the dose rates: 287 mGy/min), the percentages of apoptotic and G0/G1 phase cells increased significantly in the D2 group as compared with those in the sham-irradiaton group, while the percentages of S phase cells decreased significantly; however,the percentages of apoptotic and G0/G1 phase cells in the D1 + D2 group decreased in varying degrees as compared with those in the D2 group,while the percentages of S phase cells increased significantly.
The above results suggest that EL-4 cells were irradiated with 25– 100 mGy (dose rates: 6.25– 50 mGy/min) 3– 24 h before 0.5– 2.0 Gy (dose rate: 287 mGy/min) exposure, the adaptive response of cell apoptosis and cell cycle progression could be induced.
2 Changes of p53, ATM, DNA-PKcs and PARP-1 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR. The EL-4 cells were divided into the following groups: sham-irradiaton, D2 (1, 1.5 and 2 Gy), D1 + D2 (75 mGy + 1 Gy, 75 mGy + 1.5 Gy and 75 mGy + 2 Gy), block agents (Wortmannin or 3-AB) + D2 and block agents (wortmannin or 3-AB) + D1 + D2 groups. Flow cytometer and RT-PCR techniques were used in this experiment to study the change of p53, ATM, DNA-PKcs and PARP-1 mRNA and protein expressions in the adaptive response induced by LDR.
2.1 Changes of p53 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with that in sham irradiation group, p53 protein expression in D2 group increased significantly, while that in D1 + D2 group was lower than that in D2 group obviously. This means that p53 protein changed significantly in adaptive response. The results show that p53 play important effects in the adaptive response.
2.2 Changes of ATM and DNA-PKcs mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with those in sham irradiation group, ATM and DNA-PKcs mRNA and protein expressions in D2 group increased significantly; while those in D1 + D2 group was higher than those in D2 group, but there was no significant difference between these two groups. ATM and DNA-PKcs mRNA and protein expressions in W + D2 group was signifivantly lower than those in the D2 group, and those in W+D1+D2 group was significantly lower than that in D1 + D2 group. There was the adaptive response in W + D2 and W + D1 + D2 group.
The results showed that ATM and DNA-PKcs mRNA and protein expressions changed little in adaptive response. Wortmannin could mimic the adaptive response induced by low dose radiation against subsequent attack radiation of larger doses. Wortmannin inhibited the gene expressions of ATM and DNA-PKcs, but it still could induce adaptability, which showed wortmannin had no effects on the adaptive response. This means that ATM and DNA-PKcs didn’t play decisive effects in the adaptive response.
2.3 Changes of PARP-1 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with those in sham irradiation group, PARP-1 mRNA and protein expressions in D2 group increased significantly, while those in D1 + D2 group were higher than those in D2 group significantly. PARP-1 mRNA and protein expressions in 3-AB + D2 group decreased significantly as compared with those in D2 group. And PARP-1 mRNA and protein expressions were significantly lower than those in the D1 + D2 group. 3-AB didn’t induce the adaptive response.
The results showed that PARP-1 changed significantly in the adaptive response. The adaptive response can’t be induced by 3-AB. This means that PARP-1 play important effects in the adaptive response.
The above results show that DNA damage repair might be the main mechanism in the adaptive response induced by LDR. PARP-1 and p53 play important effects in the adaptive effects and p53 play the critical effects in the signal transduction of the adaptive response.
本实验采用分子生物学手段,在离体水平观察低剂量辐射诱导EL-4细胞凋亡及细胞周期进程的适应性反应,伴随其相关基因蛋白和mRNA水平的变化。同时,应用ATM和DNA-PK阻断剂渥曼青霉素,PARP-1阻断剂3-AB进一步证实上述基因在适应性反应中的作用。
实验表明,低剂量辐射可以在体外诱导EL-4细胞凋亡及细胞周期进程的适应性反应。在低剂量辐射诱导适应性反应中,p53表达减少,ATM和DNA-PKcs表达无明显变化,PARP-1表达增加;应用3-AB后未出现适应性反应。渥曼青霉素对适应性反应无影响,可能与渥曼青霉素作用机制有关,即其抑制ATM和DNA-PK,但不抑制p38MAPK及PKC,而后者可激活p53蛋白。
以上结果显示:p53和PARP-1基因均在适应性反应中起作用。其中,p53基因在适应性反应中起决定性作用,而ATM和DNA-PK无明显作用。表明DNA修复可能是低剂量电离辐射诱导适应性反应的主要机制。
Low dose radiation (LDR) could induce adaptive response, which has certain regularity. It has not been fully clear about the mechanism of adaptive response (AR) induced by LDR. Recent studies show that adaptive response might be mainly related with the improvement of DNA repair. At present, there’s some striking development in the study of DNA damage repair mechanism of adaptive response showed by consistent viewpoint that non-homologous end-joining (NHEJ) repair of DNA double strand break repair was the main factor in five ways of DNA damage repair to induce AR. p53 may play critical effects in this DNA repair way. It has not been very clear about the mechanism of p53, phosphatidylinositol 3-kinase (PI3K) families (ataxia-telangiectasia mutated gene, ATM; DNA-dependent protein kinase, DNA-PK) and poly-(ADP ribose) polymerase (PARP) in adaptive response, which were the main regulatory genes in NHEJ repair way. To explore further the DNA damage repair mechanism of LDR, the dose-, dose rate- and time-effects of adaptive response of apoptosis and cell cycle progression in EL-4 cells induced by low dose radiation were observed in the present experiment, and the mRNA and protein expressions of p53, ATM, DNA-PK catalytic subunit (DNA-PKcs) and PARP-1 gene were determined, at the same time, wortmannin which is the blocking agent of ATM and DNA-PK and 3-aminobenzamid (3-AB) which is PARP-1 blocking agent were used. There’s no related report in this study up to now around the world.
1 Dose-, dose rate- and time-effects of adaptive response of cell apoptosis and cell cycle progression induced by low dose radiation in EL-4 cells Lyphoma EL-4 cells were irradiated with inductive doses (doses of D1: 25, 50, 100 and 200 mGy; dose rate: 12.5 mGy/min; dose of D1: 75 mGy, dose rates: 6.25, 12.5, 25, 50, 100 and 200 mGy/min) and challenging doses (doses of D2: 0.5, 1.0, 1.5, 2.0 and 3.0 Gy, dose rate: 287 mGy/min), the intervals between D1 and D2 were 3, 6, 12, 24, 48 and 60 h, respectively. The cell apoptosis and cell cycle progression were measured with flow cytometer.
The results showed that when the doses of D1 were 25– 100 mGy (the dose rate: 12.5 mGy/min, the interval between D1 and D2: 6 h) or the dose of D1 was 75 mGy (the dose rates: 6.25– 50 mGy/min, the intervals between D1 and D2: 3 to 24 h), and the doses of D2 were 0.5– 3.0 Gy (the dose rates: 287 mGy/min), the percentages of apoptotic and G0/G1 phase cells increased significantly in the D2 group as compared with those in the sham-irradiaton group, while the percentages of S phase cells decreased significantly; however,the percentages of apoptotic and G0/G1 phase cells in the D1 + D2 group decreased in varying degrees as compared with those in the D2 group,while the percentages of S phase cells increased significantly.
The above results suggest that EL-4 cells were irradiated with 25– 100 mGy (dose rates: 6.25– 50 mGy/min) 3– 24 h before 0.5– 2.0 Gy (dose rate: 287 mGy/min) exposure, the adaptive response of cell apoptosis and cell cycle progression could be induced.
2 Changes of p53, ATM, DNA-PKcs and PARP-1 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR. The EL-4 cells were divided into the following groups: sham-irradiaton, D2 (1, 1.5 and 2 Gy), D1 + D2 (75 mGy + 1 Gy, 75 mGy + 1.5 Gy and 75 mGy + 2 Gy), block agents (Wortmannin or 3-AB) + D2 and block agents (wortmannin or 3-AB) + D1 + D2 groups. Flow cytometer and RT-PCR techniques were used in this experiment to study the change of p53, ATM, DNA-PKcs and PARP-1 mRNA and protein expressions in the adaptive response induced by LDR.
2.1 Changes of p53 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with that in sham irradiation group, p53 protein expression in D2 group increased significantly, while that in D1 + D2 group was lower than that in D2 group obviously. This means that p53 protein changed significantly in adaptive response. The results show that p53 play important effects in the adaptive response.
2.2 Changes of ATM and DNA-PKcs mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with those in sham irradiation group, ATM and DNA-PKcs mRNA and protein expressions in D2 group increased significantly; while those in D1 + D2 group was higher than those in D2 group, but there was no significant difference between these two groups. ATM and DNA-PKcs mRNA and protein expressions in W + D2 group was signifivantly lower than those in the D2 group, and those in W+D1+D2 group was significantly lower than that in D1 + D2 group. There was the adaptive response in W + D2 and W + D1 + D2 group.
The results showed that ATM and DNA-PKcs mRNA and protein expressions changed little in adaptive response. Wortmannin could mimic the adaptive response induced by low dose radiation against subsequent attack radiation of larger doses. Wortmannin inhibited the gene expressions of ATM and DNA-PKcs, but it still could induce adaptability, which showed wortmannin had no effects on the adaptive response. This means that ATM and DNA-PKcs didn’t play decisive effects in the adaptive response.
2.3 Changes of PARP-1 mRNA and protein expressions in adaptive response of EL-4 cell apoptosis and cell cycle progression induced by LDR
The results showed that as compared with those in sham irradiation group, PARP-1 mRNA and protein expressions in D2 group increased significantly, while those in D1 + D2 group were higher than those in D2 group significantly. PARP-1 mRNA and protein expressions in 3-AB + D2 group decreased significantly as compared with those in D2 group. And PARP-1 mRNA and protein expressions were significantly lower than those in the D1 + D2 group. 3-AB didn’t induce the adaptive response.
The results showed that PARP-1 changed significantly in the adaptive response. The adaptive response can’t be induced by 3-AB. This means that PARP-1 play important effects in the adaptive response.
The above results show that DNA damage repair might be the main mechanism in the adaptive response induced by LDR. PARP-1 and p53 play important effects in the adaptive effects and p53 play the critical effects in the signal transduction of the adaptive response.
引文
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