化学损伤剂诱导下Fen1突变小鼠癌症发生机制的研究
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摘要
对各种癌症的观察分析发现,当不同的个体暴露于一定的含致癌物的环境时,他们倾向于发生癌症的程度是不同的。流行病学的研究表明在外界DNA损伤的刺激下,个体表现出的不同癌症发生倾向性可能和基因的多样性有关,如碱基切除修复(BER)相关基因的单核苷酸多态性。为了验证这个长久以来的假说,并进一步阐明参与BER途径中一个基因(Fen])的变化是如何导致机体对环境损伤剂敏感从而产生癌症,我们利用已建立的FEN1点突变(E160D)小鼠展开了一系列的实验研究,并分别从分子水平、细胞水平和小鼠模型三个层面对相关的机制进行了阐述。
1、构建了FEN1点突变库,并对重组蛋白的纯化方法进行了优化。我们沿用点突变的方法,将FEN1各氨基酸位点突变为丙氨酸,并将鉴定后的质粒和菌株保存入库。另外,我们还优化了FPLC蛋白纯化系统进而得到了极高纯度的重组蛋白,为后续的大量生化实验奠定了基础。
2、在体外分析了重组蛋白和MEF细胞(鼠胚胎纤维细胞)核粗提物对两种BER修复过程的中间产物类似物的酶切活性,发现E160D突变的存在会大大影响FEN1蛋白或相应MEF细胞对DNA损伤的切除能力。此外,我们还在体外比较了MEF细胞的BER修复能力并同时利用纯化的重组蛋白进行了LP-BER重建。对所得到的放射性产物进行信号强弱比较发现,E160D突变MEF细胞的BER活性要明显低于野生型细胞；该突变也同时影响了体外LP-BER重建的效率。
3、研究了在化学损伤剂(MNU和H202)处理情况下细胞水平的变化。E160D突变的MEF细胞对MNU和H202处理的敏感性更高,表现为其DNA复制叉的瓦解、DNA双链断裂(DSBs)的产生以及引发的染色体畸变,使细胞内非正常染色体(四倍体和非整倍体)的比例增加。
4、对基因改造小鼠进行一次性的DNA烷化剂(MNU)注射。在对照组小鼠生长完全正常的情况下,处理的小鼠表现出很高的肺癌发生率,其中尤以E160D纯合突变鼠的肿瘤恶性程度最高。
综上,我们认为BER相关基因(FEN1)的一个微小变化(点突变E160D)会导致机体对碱基损伤的修复能力下降,而当含有这种突变类型的个体处于化学损伤剂诱导的条件下,会更倾向于罹患癌症。
A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we used the pre-exist mouse model to demonstrate the mechanism. Here, we addressed the questions through several levels, including molecular, cellular and mouse model et.al.
1、We established a point-mutations pool of human FEN1 and then optimized the purification protocol for those recombination proteins. We mutated all the amino acids of FEN1 into Alanine by Quick-Change mutagnesis, stored the mutated plasmids and the transformed protein expression strains. Meanwhile, we optimized the protein purification protocol by using FPLC system and obtained extremely-pure FEN1 proteins, which can be used for a bundle of biochemistry assays in the future studies.
2、We demonstrated that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER;The LP-BER activity is decreased using nuclear extracts or reconstituted purified BER proteins by in vitro biochemistry assays.
3、We also observed the phenotypes after chemical induction in cellular level. E160D cells were more sensitive to the base-damaging agents methylnitrosourea (MNU) and hydrogen peroxide (H2O2), leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response to these DNA insults.
4、We further show that E160D mice are more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma.
Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.
1、构建了FEN1点突变库,并对重组蛋白的纯化方法进行了优化。我们沿用点突变的方法,将FEN1各氨基酸位点突变为丙氨酸,并将鉴定后的质粒和菌株保存入库。另外,我们还优化了FPLC蛋白纯化系统进而得到了极高纯度的重组蛋白,为后续的大量生化实验奠定了基础。
2、在体外分析了重组蛋白和MEF细胞(鼠胚胎纤维细胞)核粗提物对两种BER修复过程的中间产物类似物的酶切活性,发现E160D突变的存在会大大影响FEN1蛋白或相应MEF细胞对DNA损伤的切除能力。此外,我们还在体外比较了MEF细胞的BER修复能力并同时利用纯化的重组蛋白进行了LP-BER重建。对所得到的放射性产物进行信号强弱比较发现,E160D突变MEF细胞的BER活性要明显低于野生型细胞；该突变也同时影响了体外LP-BER重建的效率。
3、研究了在化学损伤剂(MNU和H202)处理情况下细胞水平的变化。E160D突变的MEF细胞对MNU和H202处理的敏感性更高,表现为其DNA复制叉的瓦解、DNA双链断裂(DSBs)的产生以及引发的染色体畸变,使细胞内非正常染色体(四倍体和非整倍体)的比例增加。
4、对基因改造小鼠进行一次性的DNA烷化剂(MNU)注射。在对照组小鼠生长完全正常的情况下,处理的小鼠表现出很高的肺癌发生率,其中尤以E160D纯合突变鼠的肿瘤恶性程度最高。
综上,我们认为BER相关基因(FEN1)的一个微小变化(点突变E160D)会导致机体对碱基损伤的修复能力下降,而当含有这种突变类型的个体处于化学损伤剂诱导的条件下,会更倾向于罹患癌症。
A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we used the pre-exist mouse model to demonstrate the mechanism. Here, we addressed the questions through several levels, including molecular, cellular and mouse model et.al.
1、We established a point-mutations pool of human FEN1 and then optimized the purification protocol for those recombination proteins. We mutated all the amino acids of FEN1 into Alanine by Quick-Change mutagnesis, stored the mutated plasmids and the transformed protein expression strains. Meanwhile, we optimized the protein purification protocol by using FPLC system and obtained extremely-pure FEN1 proteins, which can be used for a bundle of biochemistry assays in the future studies.
2、We demonstrated that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER;The LP-BER activity is decreased using nuclear extracts or reconstituted purified BER proteins by in vitro biochemistry assays.
3、We also observed the phenotypes after chemical induction in cellular level. E160D cells were more sensitive to the base-damaging agents methylnitrosourea (MNU) and hydrogen peroxide (H2O2), leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response to these DNA insults.
4、We further show that E160D mice are more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma.
Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.
引文
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