紫外线诱导的细胞DNA损伤模式研究
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摘要
DNA是储存与传递遗传信息的重要生物大分子，其分子的完整性对生物体生命活动至关重要。过量的紫外辐射可引起细胞内DNA碱基发生突变、DNA断裂、DNA-DNA交联、DNA-蛋白交联以及染色体畸变等损伤。DNA损伤若不能及时修复，细胞将发生癌变或死亡。不同剂量紫外线对细胞DNA的损伤模式不同，可能引起的修复机制有差别。因此，研究不同剂量紫外线诱导细胞DNA损伤模式的变化对于进一步探讨DNA损伤修复机制，预防某些修复缺陷性疾病的发生有一定的现实意义，并对遗传学、肿瘤学、衰老学和毒理学等研究具有一定的理论价值。
本文采用彗星电泳法检测紫外线对细胞DNA损伤的效应以及不同种类细胞的敏感性差异；应用彗星电泳、DCFH-DA荧光探针检测法以及NAC抗氧化剂等方法检测了低剂量紫外线对细胞DNA的损伤；采用流式细胞仪、MTT、细胞计数等方法检测了中等剂量UVC对细胞DNA的损伤；应用原子力显微镜和彗星电泳方法检测了高剂量紫外线对细胞DNA的损伤。
主要内容：
1、检测相同剂量不同功率紫外线诱导的细胞DNA损伤。彗星电泳和HE染色的实验结果表明：离体培养的K562细胞和原代培养的小鼠肝细胞经不同功率相同剂量的UVC或UVB照射后，DNA损伤程度无差异。
2、检测不同波长UV照射白血病K562细胞DNA的损伤。彗星电泳的检测结果显示：照射剂量0-440 J／m~2的UVA不会对K562细胞DNA造成即时性损伤；UVB、UVC可以造成K562细胞DNA的损伤，并在一定范围内呈现照射剂量依赖效应。UVB在20～320 J／m~2照射剂量下与细胞DNA损伤的相关性为0．9344和0．956：UVC在3．2～180 J／m~2照射剂量下与细胞DNA损伤的相关性为0．9841和0．994：相同照射剂量下UVC对细胞DNA的损伤程度显著高于UVB。
3、检测了不同细胞对UVC的敏感性。不同肿瘤细胞应答UVC损伤的敏感性存在差异：SMMC-7721细胞的敏感性高于HepG2细胞。正常细胞与肿瘤细胞应答UVC损伤的敏感性也存在差异：hepa1-6细胞的敏感性高于原代培养的小鼠肝细胞。不同活化程度的正常细胞对UVC损伤的敏感性不同：活化淋巴细胞比静息淋巴细胞敏感性高。
4、检测了不同周期时相的K562细胞对于UVC的敏感性：彗星检测发现G2期的细胞最为敏感，其次为M期、S期和G1期。
5、K562细胞和原代培养的小鼠肝细胞在低剂量UVB和UVC照射后经孵育，彗星电泳能够检测出即时检测不能发现的细胞DNA损伤。低剂量UV照射后，胞内ROS含量升高，并在细胞孵育后含量降低。实验组中加入ROS清除剂NAC后可以降低细胞DNA的损伤。这提示低剂量UV照射造成的延时损伤可能以ROS引发的损伤修复有关。
6、K562细胞经中等剂量(60 J／m~2)UVC照射后的DNA损伤在20h内修复或消失。UVC致细胞DNA损伤具有延时效应。UVC照射细胞后，随孵育时间的延长细胞DNA损伤程度加剧，2小时后DNA损伤达到最大值，孵育4小时后DNA损伤程度开始下降，孵育至20小时损伤程度恢复至未照射细胞的水平。细胞计数的结果表明，照射后12h细胞数目降至最低，而后细胞数目丌始增加。UVC照射使K562细胞周期被阻滞于G1／S期或G2／M期。
7、优化了用于原子力显微镜观察的细胞DNA提取系统。建立了用原子力显微镜观察DNA的阳性模型。
8、K562细胞经高剂量UV照射后的DNA损伤严重。高剂量UVC照射后，K562细胞DNA损伤严重，发生断裂、交联(DNA链间或链内)，K562细胞增殖能力减弱。高剂量UVB照射后，DNA小片段交联在一起。
结论：相同剂量不同功率的UVC或UVB照射后，DNA损伤程度无差异。UV造成的细胞DNA损伤与照射波段、剂量密切相关。UVC对细胞DNA的损伤能力大于UVB。UVB、UVC造成的K562细胞DNA的损伤在一定范围内呈现照射剂量依赖效应。我们得到UVB、UVC在一定剂量范围与DNA损伤之间的线性方程。UBV：y=0．1196x-0．0534，R~2=0．9344或y=0．0814x-0．0627，R~2=0．956。UVC：y=0．2018x+0．9053，R~2=0．9841或y=0．1251x+0．6914，R~2=0．994。不同细胞应答UVC损伤的敏感性存在差异，这可能与细胞的增殖速度不同有关；周期时相的细胞对UVC的敏感性不同进一步证明了这一点。
不同剂量紫外线诱导的细胞DNA损伤有不同的模式。实验发现低剂量UVB与UVC照射K562细胞和原代培养的小鼠肝细胞后经孵育，彗星电泳能够检测出即时检测不能发现的细胞DNA损伤并且细胞内ROS含量升高，进一步实验加入ROS清除剂NAC后可以降低细胞DNA的损伤，表明延时检测到的DNA损伤与ROS有一定关系。中等剂量UVC对K562细胞DNA的损伤具有延时效应并且在20小时内可以恢复。此剂量下的UVC照射后细胞周期被阻滞在G1／S期或G2／M期。应用原子力显微镜直接观测到高剂量UVC照射细胞后，K562细胞DNA损伤严重，发生断裂、交联。与UVB相比，UVC照射后细胞DNA链的直径变细，DNA链的交联可能多为链间交联。
DNA is an important biological macromolecule. The integrity of DNA is essential for cell or organism. Excessive ultraviolet radiation can cause damage in DNA, such as base pairs miss, DNA breakage, DNA-DNA cross-linking ,DNA-protein cross-linking, and chromosomal aberrations. If DNA damage can not be timely repaired, cell cancer or death would occur. Ultraviolet radiation (UV) with different energy lead to different DNA damage model, the repair mechanisms also may be not the same. Therefore, we study the DNA damage model induced by different energy UV. It has a certain practical significance for exploring DNA damage repair mechanisms and preventing some repair defective diseases.
The effects of DNA damage induced by different waves and doses of ultraviolet radiation (UV) in different cells were tested by comet assay. The cell cycle distribution was detected by the flow cytometer (FCM). The effects of intermediate dose UVC on K562 cell was investigated by MTT test, cell count and comet assay. The effects of low dose UVC on K562 cell was investigated by DCFH-DA test and comet assay. The effects of high dose UVC on K562 cell was investigated by comet assay and atomic force microscopy (AFM).
Results: 1. The primary cultured mouse hepatocyte and human leukemia K562 cells were irradiated by UVB or UVC with the same dose but different power. The experiment showed that the damage of DNA had no difference.
2. The human leukemia K562 cells were irradiated by UVA, UVB and UVC. The experiment showed that UVA couldn't induce DNA damage immediately, while UVB and UVC could induce cellular DNA damage in a dose manner, and UVC could induce DNA damage most seriously. The relativity of UVB (20-320J/m~2) between DNA damage is 0.9344/0.956. The relativity of UVC (3.2-180J/m~2) between DNA damage is 0.9841/0.994.
3. The sensitivities of different cells to UV were different. The lowest dose of UVC induced the human hepatoma SMMC-7721 cellular DNA damage was 10.4J/m~2, but the dose of UVC could induce DNA damage of h-hepatoma HepG2 cell was above 16.8J/m~2. The lowest dose of UVC induced mouse hepatoma hepal-6 cellular DNA damage was 1.6J/m~2, but for the primary cultured mouse hepatocyte was achieved to 2.4 J/m~2. The activated human lymphocyte was more sensitive than the resting human lymphocyte to UVC.
4. When synchronized K562 cells were irradiated by 60J/m~2 UVC, the cells of G2/M phase showed that it was more sensitive than others.
5. K562 and the mouse hepatocyte cells were irradiated by low dose UVC, the DNA damage was detected by comet assay after incubated 2h but not immediately. Irradiated with low dose UVB or UVC, the intracellular ROS content increased, and decreased after the cells were incubated. The DNA damage of experimental group cell can be reduced by adding NAC.
6. After irradiated by intermediate dose (60 J/m~2) UVC, the DNA damage of K562 cells represented delayed effect, and it can be repaired during 20h. Cell count and morphological observation showed that the number of K562 cells declined least after incubated 12h, and some cells damaged severely. The results of comet assay showed that the highest damage was appeared after incubated 2-4h. The cell cycle distribution was also changed after irradiated. Cells were arrested in Gl/S or G2/M.
7. After irradiated by high dose UVC or UVB, the DNA damage model of DNA breakage and DNA cross-linking was highly appeared in K562 cells.
Conclusions: The comet assay results showed that UVA couldn't induce DNA damage immediately, while UVB and UVC could induce cellular DNA damage in a dose dependent manner, and UVC could induce DNA damage most seriously. The linear equation of DNA damage and UVB: y=0.1196x-0.0534, R~2=0.9344 or y=0.0814x-0.0627, R~2=0.956. The linear equation of DNA damage and UVC: y=0.2018x+0.9053, R~2=0.9841或y=0.1251x+0.6914, R~2=0.994. The sensitivities to UV were different in different cells. The cancer cells were more sensitive to UV, and the sensitivity of cells to UV was related to its proliferation speed. When irradiated by lower dose UVC, DNA damage of K562 cell just appeared in a delayed manner, but not immediately. The delay was related to ROS. When irradiated intermediately by UVC (60 J/m~2), damage of the cell represented delayed effect, and it can be repaired during 20h. The cell cycle distribution was also changed after irradiating; cells were arrested in G1/S or G2/M. After irradiated by high dose UVC or UVB, the DNA damage mode of DNA breakage and DNA cross-linking was highly appeared in K562 cells.
本文采用彗星电泳法检测紫外线对细胞DNA损伤的效应以及不同种类细胞的敏感性差异；应用彗星电泳、DCFH-DA荧光探针检测法以及NAC抗氧化剂等方法检测了低剂量紫外线对细胞DNA的损伤；采用流式细胞仪、MTT、细胞计数等方法检测了中等剂量UVC对细胞DNA的损伤；应用原子力显微镜和彗星电泳方法检测了高剂量紫外线对细胞DNA的损伤。
主要内容：
1、检测相同剂量不同功率紫外线诱导的细胞DNA损伤。彗星电泳和HE染色的实验结果表明：离体培养的K562细胞和原代培养的小鼠肝细胞经不同功率相同剂量的UVC或UVB照射后，DNA损伤程度无差异。
2、检测不同波长UV照射白血病K562细胞DNA的损伤。彗星电泳的检测结果显示：照射剂量0-440 J／m~2的UVA不会对K562细胞DNA造成即时性损伤；UVB、UVC可以造成K562细胞DNA的损伤，并在一定范围内呈现照射剂量依赖效应。UVB在20～320 J／m~2照射剂量下与细胞DNA损伤的相关性为0．9344和0．956：UVC在3．2～180 J／m~2照射剂量下与细胞DNA损伤的相关性为0．9841和0．994：相同照射剂量下UVC对细胞DNA的损伤程度显著高于UVB。
3、检测了不同细胞对UVC的敏感性。不同肿瘤细胞应答UVC损伤的敏感性存在差异：SMMC-7721细胞的敏感性高于HepG2细胞。正常细胞与肿瘤细胞应答UVC损伤的敏感性也存在差异：hepa1-6细胞的敏感性高于原代培养的小鼠肝细胞。不同活化程度的正常细胞对UVC损伤的敏感性不同：活化淋巴细胞比静息淋巴细胞敏感性高。
4、检测了不同周期时相的K562细胞对于UVC的敏感性：彗星检测发现G2期的细胞最为敏感，其次为M期、S期和G1期。
5、K562细胞和原代培养的小鼠肝细胞在低剂量UVB和UVC照射后经孵育，彗星电泳能够检测出即时检测不能发现的细胞DNA损伤。低剂量UV照射后，胞内ROS含量升高，并在细胞孵育后含量降低。实验组中加入ROS清除剂NAC后可以降低细胞DNA的损伤。这提示低剂量UV照射造成的延时损伤可能以ROS引发的损伤修复有关。
6、K562细胞经中等剂量(60 J／m~2)UVC照射后的DNA损伤在20h内修复或消失。UVC致细胞DNA损伤具有延时效应。UVC照射细胞后，随孵育时间的延长细胞DNA损伤程度加剧，2小时后DNA损伤达到最大值，孵育4小时后DNA损伤程度开始下降，孵育至20小时损伤程度恢复至未照射细胞的水平。细胞计数的结果表明，照射后12h细胞数目降至最低，而后细胞数目丌始增加。UVC照射使K562细胞周期被阻滞于G1／S期或G2／M期。
7、优化了用于原子力显微镜观察的细胞DNA提取系统。建立了用原子力显微镜观察DNA的阳性模型。
8、K562细胞经高剂量UV照射后的DNA损伤严重。高剂量UVC照射后，K562细胞DNA损伤严重，发生断裂、交联(DNA链间或链内)，K562细胞增殖能力减弱。高剂量UVB照射后，DNA小片段交联在一起。
结论：相同剂量不同功率的UVC或UVB照射后，DNA损伤程度无差异。UV造成的细胞DNA损伤与照射波段、剂量密切相关。UVC对细胞DNA的损伤能力大于UVB。UVB、UVC造成的K562细胞DNA的损伤在一定范围内呈现照射剂量依赖效应。我们得到UVB、UVC在一定剂量范围与DNA损伤之间的线性方程。UBV：y=0．1196x-0．0534，R~2=0．9344或y=0．0814x-0．0627，R~2=0．956。UVC：y=0．2018x+0．9053，R~2=0．9841或y=0．1251x+0．6914，R~2=0．994。不同细胞应答UVC损伤的敏感性存在差异，这可能与细胞的增殖速度不同有关；周期时相的细胞对UVC的敏感性不同进一步证明了这一点。
不同剂量紫外线诱导的细胞DNA损伤有不同的模式。实验发现低剂量UVB与UVC照射K562细胞和原代培养的小鼠肝细胞后经孵育，彗星电泳能够检测出即时检测不能发现的细胞DNA损伤并且细胞内ROS含量升高，进一步实验加入ROS清除剂NAC后可以降低细胞DNA的损伤，表明延时检测到的DNA损伤与ROS有一定关系。中等剂量UVC对K562细胞DNA的损伤具有延时效应并且在20小时内可以恢复。此剂量下的UVC照射后细胞周期被阻滞在G1／S期或G2／M期。应用原子力显微镜直接观测到高剂量UVC照射细胞后，K562细胞DNA损伤严重，发生断裂、交联。与UVB相比，UVC照射后细胞DNA链的直径变细，DNA链的交联可能多为链间交联。
DNA is an important biological macromolecule. The integrity of DNA is essential for cell or organism. Excessive ultraviolet radiation can cause damage in DNA, such as base pairs miss, DNA breakage, DNA-DNA cross-linking ,DNA-protein cross-linking, and chromosomal aberrations. If DNA damage can not be timely repaired, cell cancer or death would occur. Ultraviolet radiation (UV) with different energy lead to different DNA damage model, the repair mechanisms also may be not the same. Therefore, we study the DNA damage model induced by different energy UV. It has a certain practical significance for exploring DNA damage repair mechanisms and preventing some repair defective diseases.
The effects of DNA damage induced by different waves and doses of ultraviolet radiation (UV) in different cells were tested by comet assay. The cell cycle distribution was detected by the flow cytometer (FCM). The effects of intermediate dose UVC on K562 cell was investigated by MTT test, cell count and comet assay. The effects of low dose UVC on K562 cell was investigated by DCFH-DA test and comet assay. The effects of high dose UVC on K562 cell was investigated by comet assay and atomic force microscopy (AFM).
Results: 1. The primary cultured mouse hepatocyte and human leukemia K562 cells were irradiated by UVB or UVC with the same dose but different power. The experiment showed that the damage of DNA had no difference.
2. The human leukemia K562 cells were irradiated by UVA, UVB and UVC. The experiment showed that UVA couldn't induce DNA damage immediately, while UVB and UVC could induce cellular DNA damage in a dose manner, and UVC could induce DNA damage most seriously. The relativity of UVB (20-320J/m~2) between DNA damage is 0.9344/0.956. The relativity of UVC (3.2-180J/m~2) between DNA damage is 0.9841/0.994.
3. The sensitivities of different cells to UV were different. The lowest dose of UVC induced the human hepatoma SMMC-7721 cellular DNA damage was 10.4J/m~2, but the dose of UVC could induce DNA damage of h-hepatoma HepG2 cell was above 16.8J/m~2. The lowest dose of UVC induced mouse hepatoma hepal-6 cellular DNA damage was 1.6J/m~2, but for the primary cultured mouse hepatocyte was achieved to 2.4 J/m~2. The activated human lymphocyte was more sensitive than the resting human lymphocyte to UVC.
4. When synchronized K562 cells were irradiated by 60J/m~2 UVC, the cells of G2/M phase showed that it was more sensitive than others.
5. K562 and the mouse hepatocyte cells were irradiated by low dose UVC, the DNA damage was detected by comet assay after incubated 2h but not immediately. Irradiated with low dose UVB or UVC, the intracellular ROS content increased, and decreased after the cells were incubated. The DNA damage of experimental group cell can be reduced by adding NAC.
6. After irradiated by intermediate dose (60 J/m~2) UVC, the DNA damage of K562 cells represented delayed effect, and it can be repaired during 20h. Cell count and morphological observation showed that the number of K562 cells declined least after incubated 12h, and some cells damaged severely. The results of comet assay showed that the highest damage was appeared after incubated 2-4h. The cell cycle distribution was also changed after irradiated. Cells were arrested in Gl/S or G2/M.
7. After irradiated by high dose UVC or UVB, the DNA damage model of DNA breakage and DNA cross-linking was highly appeared in K562 cells.
Conclusions: The comet assay results showed that UVA couldn't induce DNA damage immediately, while UVB and UVC could induce cellular DNA damage in a dose dependent manner, and UVC could induce DNA damage most seriously. The linear equation of DNA damage and UVB: y=0.1196x-0.0534, R~2=0.9344 or y=0.0814x-0.0627, R~2=0.956. The linear equation of DNA damage and UVC: y=0.2018x+0.9053, R~2=0.9841或y=0.1251x+0.6914, R~2=0.994. The sensitivities to UV were different in different cells. The cancer cells were more sensitive to UV, and the sensitivity of cells to UV was related to its proliferation speed. When irradiated by lower dose UVC, DNA damage of K562 cell just appeared in a delayed manner, but not immediately. The delay was related to ROS. When irradiated intermediately by UVC (60 J/m~2), damage of the cell represented delayed effect, and it can be repaired during 20h. The cell cycle distribution was also changed after irradiating; cells were arrested in G1/S or G2/M. After irradiated by high dose UVC or UVB, the DNA damage mode of DNA breakage and DNA cross-linking was highly appeared in K562 cells.
引文
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