人REV3基因在MNNG诱发的非定标突变中的作用及其转录水平调控的分子机理研究
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摘要
化学致癌物可以引起DNA损伤或非DNA损伤效应(外遗传效应)，前者如果没有被正确修复，则有可能通过跨损伤合成途径形成定标突变。非定标突变是指发生在非损伤DNA部位的突变，有可能被DNA损伤或非DNA损伤效应所诱发。
当暴露于环境因子时(比如紫外线辐射)，大肠杆菌会激活SOS反应，从而产生损伤耐受，但其后果之一是引起非定标突变，而DNA聚合酶Ⅳ、Ⅴ均参与了SOS诱发的非定标突变。DNA聚合酶Ⅳ主要引起非定标-1移码突变，DNA聚合酶Ⅴ则需要RecA*蛋白与SSB的协同，引起的非定标突变的突变谱以颠换为主(占53％)。单核苷酸置换与一个碱基缺失的比例为1:2。但是，真核生物中非定标突变的发生机制还不清楚。
我们实验室近年的工作对哺乳细胞非定标突变机制的研究初步表明，细胞在受低剂量MNNG攻击后的早期，首先发生外遗传的改变，包括45KD与62KD蛋白酪氨酸磷酸化水平的升高、JNK／SAPK通路的激活、cAMP-PKA-CREB通路的激活以及NF-κB的激活。同时在产生非定标突变的细胞中检测到基因表达的改变，进一步研究发现细胞受MNNG攻击后DNA复制保真度下降、DNA聚合酶酶谱发生改变。因此，我们推测，哺乳细胞中低保真度的跨损伤DNA聚合酶可能参与了MNNG诱导的哺乳
细胞非定标突变。初步认为，MNNG诱发非定标突变的形成是继有关细
胞信号转导通路激活后，导致相关基因表达的改变，并引起DNA聚合酶
酶谱表达的改变，最终使DNA复制保真度下降，从而使突变发生在未损
伤的DNA模板上。但是，哺乳细胞中是哪种跨损伤DNA聚合酶参与了
非定标突变还不是很清楚。本实验对人DNA聚合酶＜催化亚基的编码基
因REV3在非定标突变形成中的作用及其转录水平的调控机制进行了研
究。
结果表明，低剂量MN’NG攻击人羊膜上皮培养细胞（FL）会引起REV3
基因转录水平的表达上调，并具有时相性变化，其表达水平分别在MNNG
处理后1二小时与24小时较对照提高1．刀倍与1石5倍O＜0刀匀。这种表
达变化与我们实验室发现的MN’NG诱发的非定标突变形成的时相是基本
一致的。进一步的非定标突变分析显示，REV3基因功能被反义阻断的细
胞具有极显著的抗非定标突变的作用。在REV3基因被反义阻断的
FL－REV3”细胞中，pG诱发的非定标突变频率极显著地从27．4 X10”4
下降到4刀X10－4印＜0刀1人恢复到自发突变的水平。WesteX印迹证实
了FLREV3细胞中REV3基因功能得到了有效的反义阻断。从而首次证
实，DNA聚合酶二参与了哺乳细胞非定标突变的形成。
如前所述，低剂量MNNG会引起哺乳细胞早期的某些外遗传改变，
激活转录因子CREB、AP－l以及NF－h。本实验中的生物信息学分析显
示，人REV3基因启动子区域存在上述转录因子的结合位点。因此，我们
推测，MN’NG引起的有些转录因子的激活导致REV3基因转录水平的表达
上调。而REV3基因的激活，导致人DNA聚合酶二参与非定标突变的形
成。本实验结合计算机染色体步移技术、报告基因以及瞬时转染分析，
首次克隆了人REV3基因启动子，并研究了其对MN’NG的反应。结果表
明，在细胞受到MNNO攻击后24小时，与基础表达相比，REV3基因的
3
启动子强度极显著地增强了。进一步的REV3基因启动子缺失体分析结果
表明，REV3基因启动子对MN’NG的反应元件区域存在于位于REV3基因
上游－404～102核昔酸之间upGL3卫582重组子的20if位与2314位
Sma酶切位点之（e），而仅含有单独的CREB元件还不足以激活REV3
基因的表达，需要数个转录因子的共同调控。
综合上述研究表明，在MNNG诱发的哺乳细胞非定标突变形成过程
中，早期的外遗传改变可以最终激活人DNA聚合酶＜的催化亚基编码基
因REV3的表达，从而募集低保真度的DNA聚合酶二参与形成非定标突
变。
Chemical carcinogen can lead to DNA damaging effects or non-DNA damaging effects (epigenetic effects). The former may induce DNA lesions and result in lesion-targeted mutation by translesion DNA synthesis pathway (TLS, also can be called DNA damage tolerance) if the lesion couldn't be effectively repaired. Mutation that occurs on undamaged DNA template is designated as untargeted mutation, which may be induced by both DNA damaging effects or non-DNA damaging effects.
When bacteria E. coll. are exposed to environmental agents, such as UV light, SOS response will occur to avoid negative effect. As a result, untargeted mutation occurs due to the involvement of DNA polymerase IV and V. Pol IV alone mainly induces -1 frameshift mutagenesis, however, pol V plays a role in untargeted mutation in the presence of activated RecA protein (RecA*), single-stranded binding protein (SSB) and pol Ill's processivity beta, gamma-complex. The mutation spectrum induced of pol V is dominated by transversions (53%). The analysis of independent
mutations reveals that the ratio between single-nucleotide substitutions and one-base deletions is about 1:2. However, the mechanism of eukaryotic untargeted mutagenesis is still unclear.
Previous works in our laboratory revealed that epigenetic alteration occurs at the early stage after remove of low concentration MNNG treatment, including enhanced tryosine phosphorylation level of 45KD protein and 62KD protein, activation of JNK/SAPK and cAMP-PKA-CREB pathways and the activation of NF-KB. Meanwhile, differential gene expression can be detected in MNNG-treated mammalian cells, which is in a state of inducing untargeted mutagenesis. Further studies showed that DNA replication fidelity is decreased and there is an alteration of DNA polymerase spectrum when mammalian cells are attacked by MNNG. In addition, it is clear that the signal to activate certain signal transduction pathways is not from nucleus. Consequently, a hypothesis on mammalian untargeted mutation was given, that is, DNA polymerases with low DNA replication fidelity, as effectors, might be involved in mammalian untargeted mutation. When certain signal transduction pathways are activated by MNNG, differential gene expression is induced, and leads to activation of specific DNA polymerases, which decrease the DNA replication fidelity and finally result in mammalian untargeted mutagenesis. But it is not clear that which DNA polymerase plays a role in the process. In this study, the role of human REVS gene, which encodes the catalytic subunit of human DNA polymerase, in mammalian untargeted mutagenesis was
investigated, and the basic mechanism of transcriptional regulation of REVS was studied.
Results showed that low concentration MNNG treatment led to upregulation of REVS gene expression at transcriptional level with in FL cells. After remove of MNNG, the REVS transcriptional level was significantly increased by 1.77-fold at 12h time point and 1.65-fold at 24h time point respectively as compared to DMSO control (p < 0.05). The alteration phase of REVS transcriptional level is consistent with occurrence phase of mammalian untargeted mutation induced by MNNG, which was observed previously in our laboratory. Further analysis of untargeted mutation in this study revealed that blockage of REVS gene function by antisense REVS mRNA had an anti-mutation effect and returned to the level of spontaneous mutation frequency, with significantly decrease of untargeted mutation frequency from 27.4+10-4 to 4.0+10-4 (p < 0.01). The blockage effect of antisense REVS mRNA in transgenic cell line FL-REV3" cells was confirmed by western blotting. Thus, in the first time, this study provides the evidence that DNA polymerase,is involved in MNNG-induced mammalian untargeted mutation.
As the above-mentioned evidences, low concentration MNNG can induce early epigenetic alteration in mammalian cell, activate CREB, AP-1 and NF-KB. In this study, bioinformatic analysis found that the transcriptional binding sites for these transcriptional fa
当暴露于环境因子时(比如紫外线辐射)，大肠杆菌会激活SOS反应，从而产生损伤耐受，但其后果之一是引起非定标突变，而DNA聚合酶Ⅳ、Ⅴ均参与了SOS诱发的非定标突变。DNA聚合酶Ⅳ主要引起非定标-1移码突变，DNA聚合酶Ⅴ则需要RecA*蛋白与SSB的协同，引起的非定标突变的突变谱以颠换为主(占53％)。单核苷酸置换与一个碱基缺失的比例为1:2。但是，真核生物中非定标突变的发生机制还不清楚。
我们实验室近年的工作对哺乳细胞非定标突变机制的研究初步表明，细胞在受低剂量MNNG攻击后的早期，首先发生外遗传的改变，包括45KD与62KD蛋白酪氨酸磷酸化水平的升高、JNK／SAPK通路的激活、cAMP-PKA-CREB通路的激活以及NF-κB的激活。同时在产生非定标突变的细胞中检测到基因表达的改变，进一步研究发现细胞受MNNG攻击后DNA复制保真度下降、DNA聚合酶酶谱发生改变。因此，我们推测，哺乳细胞中低保真度的跨损伤DNA聚合酶可能参与了MNNG诱导的哺乳
细胞非定标突变。初步认为，MNNG诱发非定标突变的形成是继有关细
胞信号转导通路激活后，导致相关基因表达的改变，并引起DNA聚合酶
酶谱表达的改变，最终使DNA复制保真度下降，从而使突变发生在未损
伤的DNA模板上。但是，哺乳细胞中是哪种跨损伤DNA聚合酶参与了
非定标突变还不是很清楚。本实验对人DNA聚合酶＜催化亚基的编码基
因REV3在非定标突变形成中的作用及其转录水平的调控机制进行了研
究。
结果表明，低剂量MN’NG攻击人羊膜上皮培养细胞（FL）会引起REV3
基因转录水平的表达上调，并具有时相性变化，其表达水平分别在MNNG
处理后1二小时与24小时较对照提高1．刀倍与1石5倍O＜0刀匀。这种表
达变化与我们实验室发现的MN’NG诱发的非定标突变形成的时相是基本
一致的。进一步的非定标突变分析显示，REV3基因功能被反义阻断的细
胞具有极显著的抗非定标突变的作用。在REV3基因被反义阻断的
FL－REV3”细胞中，pG诱发的非定标突变频率极显著地从27．4 X10”4
下降到4刀X10－4印＜0刀1人恢复到自发突变的水平。WesteX印迹证实
了FLREV3细胞中REV3基因功能得到了有效的反义阻断。从而首次证
实，DNA聚合酶二参与了哺乳细胞非定标突变的形成。
如前所述，低剂量MNNG会引起哺乳细胞早期的某些外遗传改变，
激活转录因子CREB、AP－l以及NF－h。本实验中的生物信息学分析显
示，人REV3基因启动子区域存在上述转录因子的结合位点。因此，我们
推测，MN’NG引起的有些转录因子的激活导致REV3基因转录水平的表达
上调。而REV3基因的激活，导致人DNA聚合酶二参与非定标突变的形
成。本实验结合计算机染色体步移技术、报告基因以及瞬时转染分析，
首次克隆了人REV3基因启动子，并研究了其对MN’NG的反应。结果表
明，在细胞受到MNNO攻击后24小时，与基础表达相比，REV3基因的
3
启动子强度极显著地增强了。进一步的REV3基因启动子缺失体分析结果
表明，REV3基因启动子对MN’NG的反应元件区域存在于位于REV3基因
上游－404～102核昔酸之间upGL3卫582重组子的20if位与2314位
Sma酶切位点之（e），而仅含有单独的CREB元件还不足以激活REV3
基因的表达，需要数个转录因子的共同调控。
综合上述研究表明，在MNNG诱发的哺乳细胞非定标突变形成过程
中，早期的外遗传改变可以最终激活人DNA聚合酶＜的催化亚基编码基
因REV3的表达，从而募集低保真度的DNA聚合酶二参与形成非定标突
变。
Chemical carcinogen can lead to DNA damaging effects or non-DNA damaging effects (epigenetic effects). The former may induce DNA lesions and result in lesion-targeted mutation by translesion DNA synthesis pathway (TLS, also can be called DNA damage tolerance) if the lesion couldn't be effectively repaired. Mutation that occurs on undamaged DNA template is designated as untargeted mutation, which may be induced by both DNA damaging effects or non-DNA damaging effects.
When bacteria E. coll. are exposed to environmental agents, such as UV light, SOS response will occur to avoid negative effect. As a result, untargeted mutation occurs due to the involvement of DNA polymerase IV and V. Pol IV alone mainly induces -1 frameshift mutagenesis, however, pol V plays a role in untargeted mutation in the presence of activated RecA protein (RecA*), single-stranded binding protein (SSB) and pol Ill's processivity beta, gamma-complex. The mutation spectrum induced of pol V is dominated by transversions (53%). The analysis of independent
mutations reveals that the ratio between single-nucleotide substitutions and one-base deletions is about 1:2. However, the mechanism of eukaryotic untargeted mutagenesis is still unclear.
Previous works in our laboratory revealed that epigenetic alteration occurs at the early stage after remove of low concentration MNNG treatment, including enhanced tryosine phosphorylation level of 45KD protein and 62KD protein, activation of JNK/SAPK and cAMP-PKA-CREB pathways and the activation of NF-KB. Meanwhile, differential gene expression can be detected in MNNG-treated mammalian cells, which is in a state of inducing untargeted mutagenesis. Further studies showed that DNA replication fidelity is decreased and there is an alteration of DNA polymerase spectrum when mammalian cells are attacked by MNNG. In addition, it is clear that the signal to activate certain signal transduction pathways is not from nucleus. Consequently, a hypothesis on mammalian untargeted mutation was given, that is, DNA polymerases with low DNA replication fidelity, as effectors, might be involved in mammalian untargeted mutation. When certain signal transduction pathways are activated by MNNG, differential gene expression is induced, and leads to activation of specific DNA polymerases, which decrease the DNA replication fidelity and finally result in mammalian untargeted mutagenesis. But it is not clear that which DNA polymerase plays a role in the process. In this study, the role of human REVS gene, which encodes the catalytic subunit of human DNA polymerase, in mammalian untargeted mutagenesis was
investigated, and the basic mechanism of transcriptional regulation of REVS was studied.
Results showed that low concentration MNNG treatment led to upregulation of REVS gene expression at transcriptional level with in FL cells. After remove of MNNG, the REVS transcriptional level was significantly increased by 1.77-fold at 12h time point and 1.65-fold at 24h time point respectively as compared to DMSO control (p < 0.05). The alteration phase of REVS transcriptional level is consistent with occurrence phase of mammalian untargeted mutation induced by MNNG, which was observed previously in our laboratory. Further analysis of untargeted mutation in this study revealed that blockage of REVS gene function by antisense REVS mRNA had an anti-mutation effect and returned to the level of spontaneous mutation frequency, with significantly decrease of untargeted mutation frequency from 27.4+10-4 to 4.0+10-4 (p < 0.01). The blockage effect of antisense REVS mRNA in transgenic cell line FL-REV3" cells was confirmed by western blotting. Thus, in the first time, this study provides the evidence that DNA polymerase,is involved in MNNG-induced mammalian untargeted mutation.
As the above-mentioned evidences, low concentration MNNG can induce early epigenetic alteration in mammalian cell, activate CREB, AP-1 and NF-KB. In this study, bioinformatic analysis found that the transcriptional binding sites for these transcriptional fa
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52. Casimiro C. [Etiopathogenic factors in colorectal cancer. Nutritional and life-style aspects. 2.]. Nutr Hosp 2002; 17: 128-138.
53. Ohashi E, Ogi T, Kusumoto R, Iwai S, Masutani C, Hanaoka F, Ohmori H. Error-prone bypass of certain DNA lesions by the human DNA polymerase k. Gene Dev 2000; 14: 1589?594.
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55. Johnson RE, Prakash S, Prakash L. Efficient Bypass of a Thymine-Thymine Dimer by Yeast DNA Polymerase, Pol η. Science 1999; 283: 1001-1004.
56. Boesen JJ, Stuivenberg S, Thyssens CH, Panneman H, Darroudi F, Lohman PH, Simons JW. Stress response induced by DNA damage leads to specific, delayed and untargeted mutations. Mol Gen Genet 1992; 234: 217-227.
57. Brooks N, McHugh PJ, Lee M, Hartley JA. Alteration in the choice of DNA repair pathway with increasing sequence selective DNA alkylation in the minor groove. Chem Biol 2000; 7: 659-668.
58. Cornelis JJ, Su ZZ, Rommelaere J. Direct and indirect effects of ultraviolet light on the mutagenesis of parvovirus H-1 in human cells. EMBO J 1982; 1: 693-699.
59. Kim SR, Matsui K, Yamada M, Gruz P, Nohmi T. Roles of chromosomal and episomal dinB genes encoding DNA pol Ⅳ in targeted and untargeted mutagenesis in Escherichia coli. Mol Genet Genomics 2001; 266:207-215.
60. Knaap AG, Simons JW. Ascertainment of the effect of differential growth rates of mutants on observed mutant frequencies in X-irradiated mammalian cells. An indication for the occurrence of X-ray-induced untargeted mutagenesis. Mutat Res 1983; 110: 413-422.
61. Kunz BA, Glickman BW. The role of pyrimidine dimers as
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62. Lawrence CW, Christensen RB. The mechanism of untargeted mutagenesis in UV-irradiated yeast. Mol Gen Genet 1982, 186:1-9.
63. Maor-Shoshani A, Reuven NB, Tomer G, Livneh Z. Highly mutagenic replication by DNA polymerase V (UmuC) provides a mechanistic basis for SOS untargeted mutagenesis. Proc Natl Acad Sci U S A 2000; 97:565-570.
64. Otterlei M, Kavli B, Standal R, Skjelbred C, Bharati S, Krokan HE. Repair of chromosomal abasic sites in vivo involves at least three different repair pathways. EMBO J 2000; 19:5542-5551.
65. Pham P, Bertram JG; O'Donnell M, Woodgate R, Goodman MF. A model for SOS-lesion-targeted mutations in Escherichia coli. Nature 2001, 409:366-370.
66. Feng Z, Yu Y, Chen X. Mismatch repair in MNNG-induced genetically instable monkey kidney vero cell. Acta Biol Exp Sin 1998; 31:217-221.
67. Tang M, Bruck I, Eritja R, Turner J, Frank EG, Woodgate R, O'Donnell M, Goodman MF. Biochemical basis of SOS-induced mutagenesis in Escherichia coli: reconstitution of in vitro lesion bypass dependent on the UmuD'2C mutagenic complex and RecA protein. Proc Natl Acad Sci U S A 1998; 95:9755-9760.
68. Wagner J, Gruz P, Kim SR, Yamada M, Matsui K, Fuchs RP,
Nohmi T. The dinB gene encodes a novel E. coli DNA polymerase, DNA pol Ⅳ, involved in mutagenesis. Mol Cell 1999; 4:281-286.
69. Wagner J, Nohmi T. Escherichia coli DNA polymerase Ⅳ mutator activity: genetic requirements and mutational specificity. J Bacteriol 2000; 182:4587-4595.
70. Zhang Y, Yuan F, Xin H, Wu X, Rajpal DK, Yang D, Wang Z. Human DNA polymerase kappa synthesizes DNA with extraordinarily low fidelity. Nucleic Acids Res 2000; 28:4147-4156.
71. Kim SR, Maenhaut-Michel G, Yamada M, Yamamoto Y, Matsui K, Sofuni T, Nohmi T, Ohmori H. Multiple pathways for SOS-induced mutagenesis in Escherichia coli: an overexpression of dinB/dinP results in strongly enhancing mutagenesis in the absence of any exogenous treatment to damage DNA. Proc Natl Acad Sci USA 1997; 94:13792-13797.
72. Zhang X, Yu Y, Chen X. Evidence for nontargeted mutagenesis in a monkey kidney cell line and analysis of its sequence specificity using a shuttle-vector plasmid. Mutat Res 1994; 323:105-112.
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74. Sun X, Yu Y, Chen X. Phasic analysis of MNNG induced
nontargeted mutation in mammalian cells. Chin J Pharmacol Toxicol 1996; 10:77-78(in Chinese).
75. Lu J, Yu Y, Xie H. Alteration of protein tyrosine phosphorylation in vero cells induced by N-methyl-N'-nitro-N-nitrosoguanidine. Chin J Pharmacol Toxicol 2000; 14:49-53(in Chinese).
76. Lu J, Yu Y, Xie H. Activation of JNK/SAPK pathway in vero cells induced by N-methyl-N′-nitro-N-nitrosoguanidine. Chin J Pathophysiol 2000; 16:481-485 (in Chinese).
77. Hu W, Yu Y, Zhang X. Differential gene expression induced by N-methyl-N′-nitro-N-nitrosoguanidine in vero cell and tentative identification of relevant cDNA fragments. Chin J Pharmacol Toxicol 1998; 12:62-66(in Chinese).
78. Jin J, Yu Y, Qian Y. Difference in protein expression in vero cells after antisense-blocking genes involved in the suppression of non-targeted mutagenesis. Acta Biochim Biophys Sin 2001; 33:696-702(in Chinese).
79. Feng Z, Yu Y, Chen X. mRNA expression of DNA polymerase-β in MNNG induced genetically unstable cells. Chin J Phathophysiol 1999; 15:699-702(in Chinese).
80. Okada T, Sonoda E, Yamashita YM, Koyoshi S, Tateishi S, Yamaizumi M, Takata M, Ogawa O, Takeda S. Involvement of vertebrate polkappa in Rad18-independent postreplication repair of UV damage. J Biol Chem 2002; 277:48690-48695.
81. Minko IG, Washington MT, Kanuri M, Prakash L, Prakash S, Lloyd RS. Translesion Synthesis past Acrolein-derived DNA
Adduct, gamma -Hydroxypropanodeoxyguanosine, by Yeast and Human DNA Polymerase eta. J Biol Chem 2003; 278:784-790.
82. Bartal M. Health effects of tobacco use and exposure. Monaldi Arch Chest Dis 2001; 56:545-554.
83. Woodgate R. A plethora of lesion-replicating DNA polymerases. Gene Dev 1999; 13:2191-2195.
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