CHEK2与REV3L基因多态的肺癌易感性关联与机制研究
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摘要
肺癌的发生是一个多因素、多阶段、长期相互作用的结果。肺癌的发生与环境暴露引起DNA损伤后的修复能力密切相关,而细胞周期检控点是维持细胞基因组稳定性的一个重要机制,其中DNA损伤检控点能检测细胞在生命活动过程中出现的DNA损伤并引发细胞周期阻滞,为修复损伤提供足够的时间。CHEK2基因在细胞周期调控中发挥了重要作用；当DNA出现损伤时,ATM与ATR激活CHEK2蛋白,后者将这一信号传递给能磷酸化E2F-1、BRCA1和P53等多个蛋白,启动细胞周期检验点调控。目前已发现CHEK2基因突变与乳腺癌、前列腺癌、结肠癌等多种肿瘤的发生具有密切的关系。
我们推测CHEK2基因启动子上的遗传变异可能会影响CHEK2基因最终的表达量,影响个体肺癌易感性的差异,为了检验这一假设,我们采用了病例-对照的研究方法,选择了该基因近端启动子上-122C>G与-48G>A两个单核苷酸多态(SNP)位点,利用Illumina分型方法对500例中国汉族肺癌患者和517例年龄、性别与之相匹配的正常对照进行了基因分型,研究了不同等位基因型和基因型与肺癌风险的相关性；然后在另外575例肺癌患者和589例对照人群中验证该多态和肺癌易感性的相关性。我们还进一步通过荧光素酶、凝胶迁移率电泳、染色质免疫共沉淀等方法深入的探索了阳性位点的功能。
在单位点分析中,我们发现CHEK2的启动子多态-48G>A(rs2236141)位点的等位基因型分布在病例和对照中存在显著的统计学差异,P值为0.0018。非条件logistic回归分析表明,rs2236141位点的突变杂合基因型可以显著降低患肺癌的风险(与GG基因型相比,GA基因型的校正OR=0.65,95% CI=0.40-0.85)。而rs2236142多态与肺癌风险没有显著相关性。在验证性关联分析中,我们发现rs2236141多态的基因型分布在病例和对照中也存在显著的统计学差异(P=0.014)。两次关联分析结果合并后,rs2236141多态的基因型分布在病例和对照中存在显著的统计学差异(P=0.001)；rs2236141位点的突变杂合基因型可以显著降低患肺癌的风险1.4倍(P=4×10-4)。
功能研究表明,在正常人外周血和肺组织中,A等位基因型的个体CHEK2 mRNA水平高于G等位基因型个体。由于G→A转换可能减少一个甲基化位点(CG→CA),因而该多态可能影响表观遗传学调控。荧光素酶试验表明,G/A等位型启动子表达没有显著差异；但在甲基化条件下,等位型A等位型启动子对于显著高于A等位型。凝胶迁移率电泳实验和表面等离子共振实验表明甲基化的G等位型启动子能增强转录因子的结合。采用体内染色质共沉淀实验表明,结合在该多态附近的转录因子为Sp1,且该转录因子起负调控作用。
本研究表明CHEK2基因启动子rs2236141多态与中国人群中肺癌的发病风险具有显著相关性；该多态位点为功能位点,突变型等位基因与负调控的Sp1蛋白结合力较弱,因而表达更高,具有保护作用。
跨损伤DNA合成(Translesion DNA Synthesis,TLS),属于一种复制后修复过程,主要包括DNA聚合酶κ、η、ι、ζ等。跨损伤DNA合成途径是生物体的一种应急机制,能够在DNA损伤未被修复的状态下进行复制延伸。REV3L (hREV3)是DNA聚合酶的ζ的催化亚基,是跨损伤DNA合成途径的主要参与者。近年来研究表明REV3L基因能维持基因组稳定性,但也不可避免的会引起DNA突变。因而REV3L基因的多态有可能影响REV3L基因最终的表达量,从而影响肺癌的易感性。
为了检验这一假设,我们采用了病例-对照的研究方法,选择了该基因上的15个多态位点,对南京地区500例肺癌患者和517例正常对照进行了基因分型,研究不同等位基因型和基因型与肺癌风险的相关性；然后在来自上海地区的575例肺癌患者和589例对照人群中验证该多态和肺癌易感性的相关性。我们还进一步通过荧光素酶、表面等离子共振、细胞免疫荧光实验、克隆形成实验等方法深入的探索了阳性位点的功能。
在单位点分析中,我们发现REV3L基因上rs465646、rs459809和rs1002481三个多态位点的基因型分布在病例和对照中存在显著的统计学差异。其中3'UTR 460 T>C(rs465646)多态位于3’UTR的一段保守区域中,其余两个SNP位于功能尚不清楚的内含子中。Rs465646多态的C等位型携带者显著降低肺癌发病风险(P=0.015)。我们在验证性关联分析中,我们发现rs465646多态的基因型分布在病例和对照中也存在显著的统计学差异(P=0.049)。
生物信息学预测表明,REV3L基因3’UTR上有多个microRNA(miRNA)结合位点；T>C多态会影响多个miRNA的结合。我们用表面等离子共振的方法,发现该多态位点附近与miR-25和miR-32均有结合。荧光素酶实验表明,共转染miR-25和miR-32均能显著降低含有REV3L基因3'UTR的报告基因的表达,表明上述miRNA能负调控REV3L基因的表达；此外,等离子表面共振实验表明,T等位型RNA与上述两种miRNA的结合能力更强。报告基因实验结果显示C等位型表达显著高于T等位型。烟草提取物能诱导REV3L基因表达,同时伴随着miR-32表达的显著降低,而miR-25表达没有显著变化；这表明miR-32可能在REV3L的转录后调控中起主要作用。REV3L基因的过表达能降低细胞的克隆形成,减少微核率,这表明REV3L基因具有稳定基因组、抑制肿瘤增殖的作用。我们转染两种等位型RNA来竞争内源miRNA,结果表明转染T等位型RNA后细胞克隆形成更少、微核率显著降低,这表明携带T等位型个体肿瘤基因组不稳定性增高、肿瘤发展更快。我们还在46对肺癌-癌旁组织中检测了REV3L基因的表达,结果表明REV3L基因mRNA在肺癌中表达显著低于癌旁。
本研究表明REV3L基因3'UTR rs465646多态为功能位点通过改变miRNA的结合,影响了基因的表达水平,从而使得携带两种基因型的个体肺癌发病风险不同。
Lung cancer is the leading cause of cancer-related deaths worldwide and tobacco smoking is one of the most important causes of lung cancer. Since the accumulation of mutations and chromosomal aberrations are the hallmarks of cancer cells, it has been hypothesized that cancer susceptibility derives from hypomorphic variants of DNA repair and checkpoint control genes. The loss of genome-maintenance mechanisms such as DNA repair and cell cycle checkpoint control may result in chromosomal abnormalities.
Checkpoint kinase 2 (CHEK2), a tumor-suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. The list of CHEK2 mutations in cancer cells is continuously expanding and the CHEK2 gene has been postulated as a susceptibility gene for a number of other common cancers, including prostate, colorectal cancers and hematopoietic neoplasms. In recent years, CHEK2 mutations have been found in lung cance. Since CHEK2 expression is ubiquitous in mammalian cells, individual differences in lung cancer susceptibility may be determined to be the consequence of impaired CHEK2 expression. We therefore hypothesized that polymorphisms in the CHEK2 gene promoter may modify its transcription and create a susceptibility to lung cancer.
We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated its association with the risk of lung cancer in a case-control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141-48 G>A was significantly associated with lung cancer risk (P= 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P= 0.042). Quantitative PCR showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The-48 G→A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electro-mobility shift assays (EMSA) and surface plasmon resonance (SPR) revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation (ChIP) to confirm that the relevant transcription factor was Spl. Using lung tissue heterozygous for the G/A SNP, we found that Spl acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.
Lung cancer remains the leading cause of cancer-related deaths worldwide. The environment, especially tobacco smoke has proved to be the most important trigger of lung cancer. However, only a fraction of smokers develop lung cancer, suggesting synergy of genetic susceptibility with environment.
Cells constantly encounter various carcinogens or cytoxic agents. These compounds directly or indirectly provoke DNA damage creating mutations, DNA cross-links or DNA strand breaks, which lead to DNA instability. Eukaryotic cells from yeast to human possess DNA post-replication repair (PPR) or DNA damage tolerance system. Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major postreplicational repair pathways. The ubiquitous translesion DNA synthesis consists of a series of specialized polymerases, including polymeraseκ,ζ,ηandι.
REV3Lp, the catalytic subunit of DNA polymerase zeta is the major participant in translesion DNA synthesis (TLS). Recent evidence suggests that REV3L plays an important role in the maintenance of genome stability despite its mutagenic characteristics. Such function makes it a genetic susceptibility gene for cancers. Here, we investigated 15 common polymorphisms in the REV3L gene in a case-control study of 500 incident lung cancer patients and 517 cancer-free controls in a Chinese population. Single locus analysis revealed that three SNPs (rs465646, rs459809 and rs1002481) were significantly associated with the risk for lung cancer. One of the strongest associations comes from the 3'UTR 460 T>C polymorphism (rs465646). The C-allele was significantly associated with reduced lung cancer risk (P= 0.015). Similar results were obtained in a follow-up replication study in another 575 lung cancer cases and 589 controls (P= 0.049). This 3'UTR 460 T>C variation was predicted to modulate the binding of several micorRNAs. We found that the T-allele demonstrated stronger binding affinity for miR-25 and miR-32, which was accompanied by significantly weaker reporter expression level. Cigarette smoke extracts could upregulate and downregulate the expression of REV3L and miR-32, respectively. Overexpression of REV3L attenuated foci and micronucleus formation, indicating the tumor-suppressing role of REV3L. Our data also shows a significant reduction of REV3L gene expression in 46 lung carcinomas when compared to normal adjacent tissues. These results support our hypothesis that the REV3L rs465646 variant modifies lung cancer susceptibility in the Chinese population by affecting microRNA-mediated regulation.
Extending our previous association study, we have successfully identified the risk contributing polymorphism in the REV3L gene and a possible underlying mechanism in carcinogenesis.
我们推测CHEK2基因启动子上的遗传变异可能会影响CHEK2基因最终的表达量,影响个体肺癌易感性的差异,为了检验这一假设,我们采用了病例-对照的研究方法,选择了该基因近端启动子上-122C>G与-48G>A两个单核苷酸多态(SNP)位点,利用Illumina分型方法对500例中国汉族肺癌患者和517例年龄、性别与之相匹配的正常对照进行了基因分型,研究了不同等位基因型和基因型与肺癌风险的相关性；然后在另外575例肺癌患者和589例对照人群中验证该多态和肺癌易感性的相关性。我们还进一步通过荧光素酶、凝胶迁移率电泳、染色质免疫共沉淀等方法深入的探索了阳性位点的功能。
在单位点分析中,我们发现CHEK2的启动子多态-48G>A(rs2236141)位点的等位基因型分布在病例和对照中存在显著的统计学差异,P值为0.0018。非条件logistic回归分析表明,rs2236141位点的突变杂合基因型可以显著降低患肺癌的风险(与GG基因型相比,GA基因型的校正OR=0.65,95% CI=0.40-0.85)。而rs2236142多态与肺癌风险没有显著相关性。在验证性关联分析中,我们发现rs2236141多态的基因型分布在病例和对照中也存在显著的统计学差异(P=0.014)。两次关联分析结果合并后,rs2236141多态的基因型分布在病例和对照中存在显著的统计学差异(P=0.001)；rs2236141位点的突变杂合基因型可以显著降低患肺癌的风险1.4倍(P=4×10-4)。
功能研究表明,在正常人外周血和肺组织中,A等位基因型的个体CHEK2 mRNA水平高于G等位基因型个体。由于G→A转换可能减少一个甲基化位点(CG→CA),因而该多态可能影响表观遗传学调控。荧光素酶试验表明,G/A等位型启动子表达没有显著差异；但在甲基化条件下,等位型A等位型启动子对于显著高于A等位型。凝胶迁移率电泳实验和表面等离子共振实验表明甲基化的G等位型启动子能增强转录因子的结合。采用体内染色质共沉淀实验表明,结合在该多态附近的转录因子为Sp1,且该转录因子起负调控作用。
本研究表明CHEK2基因启动子rs2236141多态与中国人群中肺癌的发病风险具有显著相关性；该多态位点为功能位点,突变型等位基因与负调控的Sp1蛋白结合力较弱,因而表达更高,具有保护作用。
跨损伤DNA合成(Translesion DNA Synthesis,TLS),属于一种复制后修复过程,主要包括DNA聚合酶κ、η、ι、ζ等。跨损伤DNA合成途径是生物体的一种应急机制,能够在DNA损伤未被修复的状态下进行复制延伸。REV3L (hREV3)是DNA聚合酶的ζ的催化亚基,是跨损伤DNA合成途径的主要参与者。近年来研究表明REV3L基因能维持基因组稳定性,但也不可避免的会引起DNA突变。因而REV3L基因的多态有可能影响REV3L基因最终的表达量,从而影响肺癌的易感性。
为了检验这一假设,我们采用了病例-对照的研究方法,选择了该基因上的15个多态位点,对南京地区500例肺癌患者和517例正常对照进行了基因分型,研究不同等位基因型和基因型与肺癌风险的相关性；然后在来自上海地区的575例肺癌患者和589例对照人群中验证该多态和肺癌易感性的相关性。我们还进一步通过荧光素酶、表面等离子共振、细胞免疫荧光实验、克隆形成实验等方法深入的探索了阳性位点的功能。
在单位点分析中,我们发现REV3L基因上rs465646、rs459809和rs1002481三个多态位点的基因型分布在病例和对照中存在显著的统计学差异。其中3'UTR 460 T>C(rs465646)多态位于3’UTR的一段保守区域中,其余两个SNP位于功能尚不清楚的内含子中。Rs465646多态的C等位型携带者显著降低肺癌发病风险(P=0.015)。我们在验证性关联分析中,我们发现rs465646多态的基因型分布在病例和对照中也存在显著的统计学差异(P=0.049)。
生物信息学预测表明,REV3L基因3’UTR上有多个microRNA(miRNA)结合位点；T>C多态会影响多个miRNA的结合。我们用表面等离子共振的方法,发现该多态位点附近与miR-25和miR-32均有结合。荧光素酶实验表明,共转染miR-25和miR-32均能显著降低含有REV3L基因3'UTR的报告基因的表达,表明上述miRNA能负调控REV3L基因的表达；此外,等离子表面共振实验表明,T等位型RNA与上述两种miRNA的结合能力更强。报告基因实验结果显示C等位型表达显著高于T等位型。烟草提取物能诱导REV3L基因表达,同时伴随着miR-32表达的显著降低,而miR-25表达没有显著变化；这表明miR-32可能在REV3L的转录后调控中起主要作用。REV3L基因的过表达能降低细胞的克隆形成,减少微核率,这表明REV3L基因具有稳定基因组、抑制肿瘤增殖的作用。我们转染两种等位型RNA来竞争内源miRNA,结果表明转染T等位型RNA后细胞克隆形成更少、微核率显著降低,这表明携带T等位型个体肿瘤基因组不稳定性增高、肿瘤发展更快。我们还在46对肺癌-癌旁组织中检测了REV3L基因的表达,结果表明REV3L基因mRNA在肺癌中表达显著低于癌旁。
本研究表明REV3L基因3'UTR rs465646多态为功能位点通过改变miRNA的结合,影响了基因的表达水平,从而使得携带两种基因型的个体肺癌发病风险不同。
Lung cancer is the leading cause of cancer-related deaths worldwide and tobacco smoking is one of the most important causes of lung cancer. Since the accumulation of mutations and chromosomal aberrations are the hallmarks of cancer cells, it has been hypothesized that cancer susceptibility derives from hypomorphic variants of DNA repair and checkpoint control genes. The loss of genome-maintenance mechanisms such as DNA repair and cell cycle checkpoint control may result in chromosomal abnormalities.
Checkpoint kinase 2 (CHEK2), a tumor-suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. The list of CHEK2 mutations in cancer cells is continuously expanding and the CHEK2 gene has been postulated as a susceptibility gene for a number of other common cancers, including prostate, colorectal cancers and hematopoietic neoplasms. In recent years, CHEK2 mutations have been found in lung cance. Since CHEK2 expression is ubiquitous in mammalian cells, individual differences in lung cancer susceptibility may be determined to be the consequence of impaired CHEK2 expression. We therefore hypothesized that polymorphisms in the CHEK2 gene promoter may modify its transcription and create a susceptibility to lung cancer.
We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated its association with the risk of lung cancer in a case-control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141-48 G>A was significantly associated with lung cancer risk (P= 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P= 0.042). Quantitative PCR showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The-48 G→A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electro-mobility shift assays (EMSA) and surface plasmon resonance (SPR) revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation (ChIP) to confirm that the relevant transcription factor was Spl. Using lung tissue heterozygous for the G/A SNP, we found that Spl acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.
Lung cancer remains the leading cause of cancer-related deaths worldwide. The environment, especially tobacco smoke has proved to be the most important trigger of lung cancer. However, only a fraction of smokers develop lung cancer, suggesting synergy of genetic susceptibility with environment.
Cells constantly encounter various carcinogens or cytoxic agents. These compounds directly or indirectly provoke DNA damage creating mutations, DNA cross-links or DNA strand breaks, which lead to DNA instability. Eukaryotic cells from yeast to human possess DNA post-replication repair (PPR) or DNA damage tolerance system. Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major postreplicational repair pathways. The ubiquitous translesion DNA synthesis consists of a series of specialized polymerases, including polymeraseκ,ζ,ηandι.
REV3Lp, the catalytic subunit of DNA polymerase zeta is the major participant in translesion DNA synthesis (TLS). Recent evidence suggests that REV3L plays an important role in the maintenance of genome stability despite its mutagenic characteristics. Such function makes it a genetic susceptibility gene for cancers. Here, we investigated 15 common polymorphisms in the REV3L gene in a case-control study of 500 incident lung cancer patients and 517 cancer-free controls in a Chinese population. Single locus analysis revealed that three SNPs (rs465646, rs459809 and rs1002481) were significantly associated with the risk for lung cancer. One of the strongest associations comes from the 3'UTR 460 T>C polymorphism (rs465646). The C-allele was significantly associated with reduced lung cancer risk (P= 0.015). Similar results were obtained in a follow-up replication study in another 575 lung cancer cases and 589 controls (P= 0.049). This 3'UTR 460 T>C variation was predicted to modulate the binding of several micorRNAs. We found that the T-allele demonstrated stronger binding affinity for miR-25 and miR-32, which was accompanied by significantly weaker reporter expression level. Cigarette smoke extracts could upregulate and downregulate the expression of REV3L and miR-32, respectively. Overexpression of REV3L attenuated foci and micronucleus formation, indicating the tumor-suppressing role of REV3L. Our data also shows a significant reduction of REV3L gene expression in 46 lung carcinomas when compared to normal adjacent tissues. These results support our hypothesis that the REV3L rs465646 variant modifies lung cancer susceptibility in the Chinese population by affecting microRNA-mediated regulation.
Extending our previous association study, we have successfully identified the risk contributing polymorphism in the REV3L gene and a possible underlying mechanism in carcinogenesis.
引文
[1]Jha, P. (2009). Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer 9,655-664.
[2]Thun, M. J., DeLancey, J.O., Center, M. M., Jemal, A., and Ward, E. M. The global burden of cancer:priorities for prevention. Carcinogenesis 31,100-110.
[3]Parkin,D.M., Bray,F., Ferlay,J., and Pisani,P. (2005) Global cancer statistics,2002. CA Cancer J Clin,55,74-108.
[4]邹小农.(2007)中国肺癌流行病学[J].中华肿瘤防治杂志.14(12)：881-883
[5]Doll, R., Peto, R., Boreham, J., and Sutherland, I. (2004). Mortality in relation to smoking:50 years' observations on male British doctors. BMJ 328,1519.
[6]陈万青,张思维,李连弟,等.(2006)中国部分市县1998-2002年肺癌的发病与死亡[J].中国肿瘤,15(9)：570-574.
[7]Zienolddiny, S., Campa, D., Lind, H., Ryberg, D., Skaug, V., Stangeland, L., Phillips, D.H., Canzian, F. and Haugen, A. (2006) Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis,27,560-567.
[8]Hoeijmakers, J.H. (2007) Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. Mech.Ageing Dev,128, 460-462.
[9]Bartek, J. and Lukas, J. (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell,3,421-429.
[10]Ahn, J., Urist, M. and Prives, C. (2004) The Chk2 protein kinase. DNA Repair (Amst),3,1039-1047.
[11]Shiloh, Y. (2003) ATM and related protein kinases:safeguarding genome integrity. Nat. Rev. Cancer,3,155-168.
[12]Chaturvedi, P., Eng, W.K., Zhu, Y., Mattern, M.R., Mishra, R., Hurle, M.R., Zhang, X., Annan, R.S., Lu, Q., Faucette, L.F., Scott, G.F., Li, X., Carr, S.A., Johnson, R.K., Winkler, J.D. and Zhou, B.B. (1999) Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene,18, 4047-4054.
[13]S.T. Kim, D.S. Lim, C.E. Canman, M.B. Kastan, Substrate specificities and identification of putative substrates of ATM kinase family members, J Biol Chem 274 (1999)37538-37543.
[14]T. O'Neill, A.J. Dwyer, Y. Ziv, D.W. Chan, S.P. Lees-Miller, R.H. Abraham, J.H. Lai, D. Hill, Y. Shiloh, L.C. Cantley, G.A. Rathbun, Utilization of oriented peptide libraries to identify substrate motifs selected by ATM, J Biol Chem 275 (2000) 22719-22727.
[15]J. Li, G.I. Lee, S.R. Van Doren, J.C. Walker, The FHA domain mediates phosphoprotein interactions, J Cell Sci 113 (Pt 23) (2000) 4143-4149.
[16]S. Matsuoka, G. Rotman, A. Ogawa, Y. Shiloh, K. Tamai, S.J. Elledge, Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro, Proc Natl Acad Sci USA 97 (2000) 10389-10394.
[17]Matsuoka, S., Nakagawa, T., Masuda, A., Haruki, N., Elledge, S.J. and Takahashi, T. (2001) Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res.,61,5362-5365.
[18]Cybulski, C., Gorski, B., Huzarski, T., Masojc, B., Mierzejewski, M., Debniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., Zlowocka, E., Lenner, M., Grabowska, E., Nej, K., Castaneda, J., Medrek, K., Szymanska, A., Szymanska, J., Kurzawski, G., Suchy, J., Oszurek, O., Witek, A., Narod, S.A. and Lubinski, J. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet.,75,1131-1135.
[19]Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J.M., McDonnell, S.K., Qian, C., Marks, A.F., Slager, S.L., Peterson, B.J., Smith, D.I., Cheville, J.C., Blute, M.L., Jacobsen, S.J., Schaid, D.J., Tindall, D.J., Thibodeau, S.N. and Liu, W. (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72,270-280.
[20]Lipton, L., Fleischmann, C., Sieber, O.M., Thomas, H.J., Hodgson, S.V., Tomlinson, I.P. and Houlston, R.S. (2003) Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett.,200,149-152.
[21]54] T. O'Neill, L. Giarratani, P. Chen, L. Iyer, C.H. Lee, M. Bobiak, F. Kanai, B.B. Zhou, J.H. Chung, G.A. Rathbun. (2002) Determination of Substrate Motifs for Human Chkl and hCdsl/Chk2 by the Oriented Peptide Library Approach, J Biol Chem.,277,16102-16115.
[22]G.J. Seo, S.E. Kim, Y.M. Lee, J.W. Lee, J.R. Lee, M.J. Hahn, S.T. Kim. (2003) Determination of substrate specificity and putative substrates of Chk2 kinase, Biochem Biophys Res Commun.,304,339-343.
[23]Bell, D.W., Varley, J.M., Szydlo, T.E., Kang, D.H., Wahrer, D.C., Shannon, K.E., Lubratovich, M., Verselis, S.J., Isselbacher, K.J., Fraumeni, J.F., Birch, J.M., Li, F.P., Garber, J.E. and Haber, D.A. (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science,286,2528-2531.
[24]Meijers-Heijboer, H., van den Ouweland, A., Klijn, J., Wasielewski, M., de Snoo, A., Oldenburg, R., Hollestelle, A., Houben, M., Crepin, E., van Veghel-Plandsoen, M., Elstrodt, F., van Duijn, C., Bartels, C., Meijers, C., Schutte, M., McGuffog, L. Thompson, D., Easton, D., Sodha, N., Seal, S., Barfoot, R., Mangion, J., Chang-Claude, J., Eccles, D., Eeles, R., Evans, D.G., Houlston, R., Murday, V., Narod, S., Peretz, T., Peto, J., Phelan, C., Zhang, H.X., Szabo, C., Devilee, P., Goldgar, D., Futreal, P.A., Nathanson, K.L., Weber, B., Rahman, N. and Stratton, M.R. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet.,31,55-59.
[25]Vahteristo, P., Bartkova, J., Eerola, H., Syrjakoski, K., Ojala, S., Kilpivaara, O., Tamminen, A., Kononen, J., Aittomaki, K., Heikkila, P., Holli, K., Blomqvist, C., Bartek, J., Kallioniemi, O.P. and Nevanlinna, H. (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet.,71, 432-438.
[26]Driver, K.E., Song, H., Lesueur, F., Ahmed, S., Barbosa-Morais, N.L., Tyrer, J.P., Ponder, B.A., Easton, D.F., Pharoah, P.D. and Dunning, A.M. (2008) Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis,29,333-341.
[27]Bahassi el, M., Penner, C.G., Robbins, S.B., Tichy, E., Feliciano, E., Yin, M., Liang, L., Deng, L., Tischfield, J.A. and Stambrook, P.J. (2007) The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model. Mutat. Res.,616,201-209.
[28]Matsuoka, S., Nakagawa, T., Masuda, A., Haruki, N., Elledge, S.J. and Takahashi, T. (2001) Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res.,61,5362-5365.
[29]Cybulski, C., Gorski, B., Huzarski, T., Masojc, B., Mierzejewski, M., Debniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., Zlowocka, E., Lenner, M., Grabowska, E., Nej, K., Castaneda, J., Medrek, K., Szymanska, A., Szymanska, J., Kurzawski, G., Suchy, J., Oszurek, O., Witek, A., Narod, S.A. and Lubinski, J. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet.,75,1131-1135.
[30]Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J.M., McDonnell, S.K., Qian, C., Marks, A.F., Slager, S.L., Peterson, B.J., Smith, D.I., Cheville, J.C., Blute, M.L., Jacobsen, S.J., Schaid, D.J., Tindall, D.J., Thibodeau, S.N. and Liu, W. (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72,270-280.
[31]Lipton, L., Fleischmann, C., Sieber, O.M., Thomas, H.J., Hodgson, S.V., Tomlinson, I.P. and Houlston, R.S. (2003) Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett.,200,149-152.
[32]Hangaishi, A., Ogawa, S., Qiao, Y., Wang, L., Hosoya, N., Yuji, K., Imai, Y., Takeuchi, K., Miyawaki, S. and Hirai, H. (2002) Mutations of Chk2 in primary hematopoietic neoplasms. Blood,99,3075-3077.
[33]Hofmann, W.K., Miller, C.W., Tsukasaki, K., Tavor, S., Ikezoe, T., Hoelzer, D., Takeuchi, S. and Koeffler, H.P. (2001) Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. Leuk Res,25,333-338.
[34]Miller, C.W., Ikezoe, T., Krug, U., Hofmann, W.K., Tavor, S., Vegesna, V., Tsukasaki, K., Takeuchi, S. and Koeffler, H.P. (2002) Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosomes Cancer,33,17-21.
[35]Su, Y., Han, W., Giraldo, C., De Li, Y. and Block, E. R. (1998). Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am. J Respir. Cell Mol. Biol.,19,819-825.
[36]Grunau, C., Clark, S. J. and Rosenthal, A. (2001). Bisulfite genomic sequencing: systematic investigation of critical experimental parameters. Nucleic Acids Res.,29, E65-5.
[37]Walsh, T., Casadei, S., Coats, K.H., Swisher, E., Stray, S.M., Higgins, J., Roach, K.C., Mandell, J., Lee, M.K., Ciernikova, S., Foretova, L., Soucek, P. and King, M.C. (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Jama,295,1379-1388.
[38]Kilpivaara, O., Vahteristo, P., Falck, J., Syrjakoski, K., Eerola, H., Easton, D., Bartkova, J., Lukas, J., Heikkila, P., Aittomaki, K., Holli, K., Blomqvist, C., Kallioniemi, O.P., Bartek, J. and Nevanlinna, H. (2004) CHEK2 variant Ⅰ157T may be associated with increased breast cancer risk. Int J Cancer,111,543-537.
[39]Kleibl, Z., Havranek,O., Hlavata, I., Novotny, J., Sevcik, J., Pohlreich, P. and Soucek, P. (2009) The CHEK2 gene Ⅰ157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eu.r J. Cancer.,45,618-624.
[40]Brennan, P., McKay, J., Moore, L., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chow, W.H., Rothman, N., Chabrier, A., Gaborieau, V., Odefrey, F., Southey, M., Hashibe, M., Hall, J., Boffetta, P., Peto, J., Peto, R. and Hung, R.J. (2007) Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers:case control study. Hum. Mol. Genet.,16,1794-1801.
[41]Cybulski, C., Masojc, B., Oszutowska, D., Jaworowska, E., Grodzki, T. Waloszczyk, P., Serwatowski, P., Pankowski, J., Huzarski, T., Byrski, T., Gorski, B., Jakubowska, A., Debniak, T., Wokolorczyk, D., Gronwald, J., Tarnowska, C., Serrano-Fernandez, P., Lubinski, J. and Narod, S.A. (2008) Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. Carcinogenesis,29,762-765.
[42]Williams, L.H., Choong, D., Johnson, S.A. and Campbell, I.G. (2006) Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers. Clin. Cancer Res.,12,6967-6972.
[43]Zhang, P., Wang, J., Gao, W., Yuan, B.Z., Rogers, J. and Reed, E. (2004) CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer. Mol. Cancer,3,14.
[44]Wang, H., Wang, S., Shen, L., Chen, Y., Zhang, X., Zhou, J., Wang, Z., Hu, C., Yue, W. and Wang, H. (2009) Chk2 down-regulation by promoter hypermethylation in human bulk gliomas. Life Sci.
[45]Kim, D.S., Kim, M.J., Lee, J.Y., Lee, S.M., Choi, J.E., Lee, S.Y. and Park, J.Y. (2009) Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features. Lung Cancer,65,247-250.
[46]Zaid, A., Hodny, Z., Li, R. and Nelson, B.D. (2001) Spl acts as a repressor of the human adenine nucleotide translocase-2 (ANT2) promoter. Eur. J. Biochem.,268, 5497-5503.
[47]Ogra, Y., Suzuki, K., Gong, P., Otsuka, F. and Koizumi, S. (2001) Negative regulatory role of Spl in metal responsive element-mediated transcriptional activation. J. Biol. Chem.,276,16534-1659.
[48]Won, J., Yim, J. and Kim, T.K. (2002) Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. Faseb J.,16,1943-1945.
[49]Esteve, P.O., Chin, H.G. and Pradhan, S. (2007) Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J. Biol. Chem.,282,2615-2625.
[50]Clark, S.J., Harrison, J., Molloy, P.L. (1997)Spl binding is inhibited by (m)Cp(m)CpG methylation.Gene.195,67-71.
[1]Parkin,D.M., Bray,F., Ferlay,J., and Pisani,P. (2005) Global cancer statistics,2002. CA Cancer J Clin,55,74-108.
[2]邹小农.(2007)中国肺癌流行病学[J].中华肿瘤防治杂志.14(12)：881-883.
[3]Ezzati, M., Henley, S. J., Lopez, A. D., and Thun, M. J. (2005). Role of smoking in global and regional cancer epidemiology:current patterns and data needs. Int J Cancer 116,963-971.
[4]高国福,姚树祥,孙秀娣等.云南锡矿工肺癌的队列研究[J].中国肺癌杂志,2002,5(2)：81-91.
[5]李鲁,孙统达,张幸,等.单纯接触温石棉人员癌症死亡队列研究[J].中华预防医学杂志,2004,38(1)：39-42.
[6]Hoeijmakers, J. H. (2007). Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. Mech Ageing Dev 128,460-462.
[7]Umar, A., and Kunkel, T. A. (1996). DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem 238,297-307.
[8]Sonoda, E., Okada, T., Zhao, G. Y., Tateishi, S., Araki, K., Yamaizumi, M., Yagi, T., Verkaik, N. S., van Gent, D. C., Takata, M., and Takeda, S. (2003). Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. Embo J 22,3188-3197.
[9]Swaminathan S. (2004). Post-replication repair:ubiquitin throws the switch. Nat Cell Biol,6,578.
[10]Friedberg, E. C., Lehmann, A. R., and Fuchs, R. P. (2005). Trading places:how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18,499-505.
[11]Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., and Prakash, L. (2000). Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature 406, 1015-1019.
[12]Venkatesan, R. N., Bielas, J. H., and Loeb, L. A. (2006). Generation of mutator mutants during carcinogenesis. DNA Repair (Amst) 5,294-302.
[13]Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F., and Kunkel, T. A. (2000). Low fidelity DNA synthesis by human DNA polymerase-eta. Nature 404,1011-1013.
[14]Zhang, Y., Yuan, F., Wu, X., and Wang, Z. (2000). Preferential incorporation of G opposite template T by the low-fidelity human DNA polymerase iota. Mol Cell Biol 20, 7099-7108.
[15]Van Sloun, P. P., Varlet, I., Sonneveld, E., Boei, J. J., Romeijn, R. J., Eeken, J. C., and De Wind, N. (2002). Involvement of mouse Rev3 in tolerance of endogenous and exogenous DNA damage. Mol Cell Biol 22,2159-2169.
[16]Johnson R.E., Washington M.T., Haracska L., Prakash S., Prakash L.(2000b) Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions. Nature 406:1015-1019.
[17]Levine R.L., Miller H., Grollman A., Ohashi E., Ohmori H., Masutani C., Hanaoka F., Moriya M.(2001) Translesion DNA synthesis catalyzed by human Pol η and Pol κ across 1,N6-ethenodeoxyadenosine. J Biol Chem.276:18717-18721
[18]Alt, A., Lammens, K., Chiocchini, C., Lammens, A., Pieck, J. C., Kuch, D., Hopfner, K. P., and Carell, T. (2007). Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science 318,967-970.
[19]Lemontt, J. F. (1972). Induction of forward mutations in mutationally defective yeast. Mol Gen Genet 119,27-42.
[20]Andersen, P. L., Xu, F., and Xiao, W. (2008). Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA. Cell Res 18,162-173.
[21]Lin, W., Wu, X., and Wang, Z. (1999). A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. Mutat Res 433,89-98.
[22]Roos, W. P., Tsaalbi-Shtylik, A., Tsaryk, R., Guvercin, F., de Wind, N., and Kaina, B. (2009). The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Mol Pharmacol 76,927-934.
[23]Wang, X., Peterson, C. A., Zheng, H., Nairn, R. S., Legerski, R. J., and Li, L. (2001). Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol Cell Biol 21,713-720. [24] Nojima, K., Hochegger, H., Saberi, A., Fukushima, T., Kikuchi, K., Yoshimura, M., Orelli, B. J., Bishop, D. K., Hirano, S., Ohzeki, M., et al. (2005). Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65,11704-11711.
[25]Kawamura K., J O.W., Bahar R., Koshikawa N., Shishikura T., Nakagawara A., Sakiyama S., Kajiwara K., Kimura M. and Tagawa M. (2001). The error-prone DNA polymerase zeta catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues. Int J Oncol 18,97-103.
[26]Wittschieben, J. P., Reshmi, S. C., Gollin, S. M., and Wood, R. D. (2006). Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res 66,134-142.
[27]Bemark, M., Khamlichi, A. A., Davies, S. L., and Neuberger, M. S. (2000). Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr Biol 10,1213-1216.
[28]Esposito, G., Godindagger, I., Klein, U., Yaspo, M. L., Cumano, A., and Rajewsky, K. (2000). Disruption of the Rev31-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality. Curr Biol 10,1221-1224.
[29]Yu, Y., Yang, J., Zhu, F., and Xu, F. (2004). Response of REV3 promoter to N-methyl-N'-nitro-N-nitrosoguanidine. Mutat Res 550,49-58
[30]Zhu, F., Jin, C. X., Song, T., Yang, J., Guo, L., and Yu, Y. N. (2003). Response of human REV3 gene to gastric cancer inducing carcinogen N-methyl-N'-nitro-N-nitrosoguanidine and its role in mutagenesis. World J Gastroenterol 9,888-893.
[31]Brondello, J. M., Pillaire, M. J., Rodriguez, C., Gourraud, P. A., Selves, J., Cazaux, C., and Piette, J. (2008). Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 27,6093-6101.
[32]Pan, Q., Fang, Y., Xu, Y., Zhang, K., and Hu, X. (2005). Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett 217,139-147.
[33]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. (2002) The structure of haplotype blocks in the human genome. Science 296:2225-2229.
[34]Barrett JC, Fry B, Maller J, Daly MJ. (2005) Haploview:analysis and visualization of LD and haplotype maps. Bioinformatics 21:263-265.
[35]Schmid, W. (1975). The micronucleus test. Mutat Res 31,9-15.
[36]Lehmann, A. R. (2005). Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579,873-876.
[37]Prakash, S., and Prakash, L. (2002). Translesion DNA synthesis in eukaryotes:a one-or two-polymerase affair. Genes Dev 16,1872-1883.
[38]Gibbs, P. E., McGregor, W. G., Maher, V. M., Nisson, P., and Lawrence, C. W. (1998). A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 95,6876-6880.
[39]Lin, W., Wu, X., and Wang, Z. (1999). A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. Mutat Res 433,89-98.
[40]Rockwell, S., Yuan, J., Peretz, S., and Glazer, P. M. (2001). Genomic instability in cancer. Novartis Found Symp 240,133-142.
[41]Datta, A., and Jinks-Robertson, S. (1995). Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 268,1616-1619.
[42]Kajiwara, K., Kimura, M., and Tagawa, M. (2001). The error-prone DNA polymerase zeta catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues. Int J Oncol 18,97-103.
[43]Krieg, A. J., Hammond, E. M., and Giaccia, A. J. (2006). Functional analysis of p53 binding under differential stresses. Mol Cell Biol 26,7030-7045.
[44]Kim, V. N., and Nam, J. W. (2006). Genomics of microRNA. Trends Genet 22,165-173.
[45]Doench, J. G., and Sharp, P. A. (2004). Specificity of microRNA target selection in translational repression. Genes Dev 18,504-511.
[46]He, L., and Hannon, G. J. (2004). MicroRNAs:small RNAs with a big role in gene regulation. Nat Rev Genet 5,522-531.
[47]Calin, G. A., and Croce, C. M. (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6,857-866.
[48]Vatolin, S., Navaratne, K., and Weil, R. J. (2006). A novel method to detect functional microRNA targets. J Mol Biol 358,983-996.
[49]Saunders, M. A., Liang, H., and Li, W. H. (2007). Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104,3300-3305.
[50]Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibe, B., Bouix, J., Caiment, F., Elsen, J. M., Eychenne, F., et al. (2006). A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38,813-818.
[51]Wang, G., van der Walt, J. M., Mayhew, G., Li, Y. J., Zuchner, S., Scott, W. K., Martin, E. R., and Vance, J. M. (2008). Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 82,283-289.
[52]Mishra, P. J., Humeniuk, R., Mishra, P. J., Longo-Sorbello, G. S., Banerjee, D., and Bertino, J. R. (2007). A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 104,13513-13518
[1]Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. Nature 411,366-374.
[2]Umar, A., and Kunkel, T. A. (1996). DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem 238,297-307.
[3]Swaminathan S. (2004). Post-replication repair:ubiquitin throws the switch. Nat Cell Biol,6,578.
[4]Hubscher, U., Maga, G., Spadari, S. (2002) Eukaryotic DNA polymerases. Annu Rev Biochem 71,133-163.
[5]Friedberg, E. C., Lehmann, A. R., and Fuchs, R. P. (2005). Trading places:how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18,499-505.
[6]Lehmann, A. R. (2005). Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579,873-876.
[7]Gibbs, P. E., McGregor, W. G., Maher, V. M., Nisson, P., and Lawrence, C. W. (1998). A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 95,6876-6880.
[8]Friedberg, E. C., Wagner, R., and Radman, M. (2002). Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science 296,1627-1630.
[9]Sonoda, E., Okada, T., Zhao, G. Y., Tateishi, S., Araki, K., Yamaizumi, M., Yagi, T. Verkaik, N. S., van Gent, D. C., Takata, M., and Takeda, S. (2003). Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. Embo J 22,3188-3197.
[10]Gan, G. N., Wittschieben, J. P., Wittschieben, B. O., and Wood, R. D. (2008). DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 18,174-183.
[11]Lawrence, C. W., and Maher, V. M. (2001). Mutagenesis in eukaryotes dependent on DNA polymerase zeta and Revlp. Philos Trans R Soc Lond B Biol Sci 356,41-46.
[12]Lawrence, C. W. (2004). Cellular functions of DNA polymerase zeta and Revl protein. Adv. Protein Chem 69:167-203.
[13]Pan, Q., Fang, Y., Xu, Y., Zhang, K., and Hu, X. (2005). Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett 217,139-147.
[14]Wang, H. B., Zhang, S. Y., Wang, S., Lv, J., Wu, W. T., Weng, L., Chen, D., Zhang, Y., Lu, Z. P., Yang, J. M., et al. (2009). REV3L confers chemoresistance to cisplatin in human gliomas:The potential of its RNAi for synergistic therapy. Neuro Oncol.
[15]Brondello, J. M., Pillaire, M. J., Rodriguez, C., Gourraud, P. A., Selves, J., Cazaux, C., and Piette, J. (2008). Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 27,6093-6101.
[16]Bavoux, C., Hoffmann, J. S., and Cazaux, C. (2005). Adaptation to DNA damage and stimulation of genetic instability:the double-edged sword mammalian DNA polymerase kappa. Biochimie 87,637-646.
[17]Lemee, F., Bavoux, C., Pillaire, M. J., Bieth, A., Machado, C. R., Pena, S. D., Guimbaud, R., Selves, J., Hoffmann, J. S., and Cazaux, C. (2007). Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase kappa in colorectal cancer. Oncogene 26,3387-3394.
[18]Ogi, T., Kannouche, P., and Lehmann, A. R. (2005). Localisation of human Y-family DNA polymerase kappa:relationship to PCNA foci. J Cell Sci 118,129-136.
[19]Masutani, C., R. Kusumoto, A. Yamada, N. Dohmae, M. Yokoi, M. Yuasa, M. Araki, S. Iwai, K. Takio, and F. Hanaoka. (1999). The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 399:700-704.
[20]Abdulovic, A. L., and S. Jinks-Robertson. (2006). The in vivo characterization of translesion synthesis across UV-induced lesions in Saccharomyces cerevisiae:insights into Pol zeta-and Pol eta-dependent frameshift mutagenesis. Genetics 172,1487-1498.
[21]Kawamoto, T., K. Araki, E. Sonoda, Y. M. Yamashita, K. Harada, K. Kikuchi, C. Masutani, F. Hanaoka, K. Nozaki, N. Hashimoto, and S. Takeda. (2005). Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell 20,793-799.
[22]McCulloch, S. D., and T. A. Kunkel. (2008). The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 18:148-161.
[23]Nair, D. T., R. E. Johnson, S. Prakash, L. Prakash, and A. K. Aggarwal. (2004). Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature 430,377-380.
[24]Blanca, G., G. Villani, I. Shevelev, K. Ramadan, S. Spadari, U. Hubscher,and G. Maga. (2004). Human DNA polymerases lambda and beta show different efficiencies of translesion DNA synthesis past abasic sites and alternative mechanisms for frameshift generation. Biochemistry 43,11605-11615.
[25]Moon, A. F., M. Garcia-Diaz, V. K. Batra, W. A. Beard, K. Bebenek, T. A. Kunkel, S. H. Wilson, and L. C. Pedersen. (2007). The X family portrait:structural insights into biological functions of X family polymerases. DNA Repair (Amsterdam) 6,1709-1725.
[26]Prakash, S., and Prakash, L. (2002). Translesion DNA synthesis in eukaryotes:a one-or two-polymerase affair. Genes Dev 16,1872-1883.
[27]Vandewiele, D., Borden, A., O'Grady, P. I., Woodgate, R., and Lawrence, C. W. (1998). Efficient translesion replication in the absence of Escherichia coli Umu proteins and 3'-5'exonuclease proofreading function. Proc Natl Acad Sci USA 95,15519-15524.
[28]Kunz, B. A., Ramachandran, K., and Vonarx, E. J. (1998). DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae. Genetics 148,1491-1505.
[29]Wittschieben, J. P., Reshmi, S. C., Gollin, S. M., and Wood, R. D. (2006). Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res 66,134-142.
[30]Bemark, M., Khamlichi, A. A., Davies, S. L., and Neuberger, M. S. (2000). Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr Biol 10,1213-1216.
[31]Wang, X., Peterson, C. A., Zheng, H., Nairn, R. S., Legerski, R. J., and Li, L. (2001). Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol Cell Biol 21,713-720.
[32]Wood, R. D., Mitchell, M., Sgouros, J., and Lindahl, T. (2001). Human DNA repair genes. Science 291,1284-1289.
[33]Nojima, K., Hochegger, H., Saberi, A., Fukushima, T., Kikuchi, K., Yoshimura, M., Orelli, B. J., Bishop, D. K., Hirano, S., Ohzeki, M., et al. (2005). Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65,11704-11711.
[34]Shen, X., Jun, S., O'Neal, L. E., Sonoda, E., Bemark, M., Sale, J. E., and Li, L (2006). REV3 and REV1 play major roles in recombination-independent repair of DNA interstrand cross-links mediated by monoubiquitinated proliferating cell nuclear antigen (PCNA). J Biol Chem 281,13869-13872.
[35]Wu, F., Lin, X., Okuda, T., and Howell, S. B. (2004). DNA polymerase zeta regulates cisplatin cytotoxicity, mutagenicity, and the rate of development of cisplatin resistance. Cancer Res 64,8029-8035.
[36]Albertella, M. R., Green, C. M., Lehmann, A. R., and O'Connor, M. J. (2005). A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res 65, 9799-9806.
[37]Lin, X., Trang, J., Okuda, T., and Howell, S. B. (2006). DNA polymerase zeta accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost DNA mismatch repair. Clin Cancer Res 12,563-568.
[38]Okuda, T., Lin, X., Trang, J., and Howell, S. B. (2005). Suppression of hREV1 expression reduces the rate at which human ovarian carcinoma cells acquire resistance to cisplatin. Mol Pharmacol 67,1852-1860.
[39]Cheung, H. W., Chun, A. C., Wang, Q., Deng, W., Hu, L., Guan, X. Y., Nicholls, J. M., Ling, M. T., Chuan Wong, Y., Tsao, S. W., et al. (2006). Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer Res 66,4357-4367.
[40]Roos, W. P., Tsaalbi-Shtylik, A., Tsaryk, R., Guvercin, F., de Wind, N., and Kaina, B. (2009). The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Mol Pharmacol 76,927-934.
[2]Thun, M. J., DeLancey, J.O., Center, M. M., Jemal, A., and Ward, E. M. The global burden of cancer:priorities for prevention. Carcinogenesis 31,100-110.
[3]Parkin,D.M., Bray,F., Ferlay,J., and Pisani,P. (2005) Global cancer statistics,2002. CA Cancer J Clin,55,74-108.
[4]邹小农.(2007)中国肺癌流行病学[J].中华肿瘤防治杂志.14(12)：881-883
[5]Doll, R., Peto, R., Boreham, J., and Sutherland, I. (2004). Mortality in relation to smoking:50 years' observations on male British doctors. BMJ 328,1519.
[6]陈万青,张思维,李连弟,等.(2006)中国部分市县1998-2002年肺癌的发病与死亡[J].中国肿瘤,15(9)：570-574.
[7]Zienolddiny, S., Campa, D., Lind, H., Ryberg, D., Skaug, V., Stangeland, L., Phillips, D.H., Canzian, F. and Haugen, A. (2006) Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis,27,560-567.
[8]Hoeijmakers, J.H. (2007) Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. Mech.Ageing Dev,128, 460-462.
[9]Bartek, J. and Lukas, J. (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell,3,421-429.
[10]Ahn, J., Urist, M. and Prives, C. (2004) The Chk2 protein kinase. DNA Repair (Amst),3,1039-1047.
[11]Shiloh, Y. (2003) ATM and related protein kinases:safeguarding genome integrity. Nat. Rev. Cancer,3,155-168.
[12]Chaturvedi, P., Eng, W.K., Zhu, Y., Mattern, M.R., Mishra, R., Hurle, M.R., Zhang, X., Annan, R.S., Lu, Q., Faucette, L.F., Scott, G.F., Li, X., Carr, S.A., Johnson, R.K., Winkler, J.D. and Zhou, B.B. (1999) Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene,18, 4047-4054.
[13]S.T. Kim, D.S. Lim, C.E. Canman, M.B. Kastan, Substrate specificities and identification of putative substrates of ATM kinase family members, J Biol Chem 274 (1999)37538-37543.
[14]T. O'Neill, A.J. Dwyer, Y. Ziv, D.W. Chan, S.P. Lees-Miller, R.H. Abraham, J.H. Lai, D. Hill, Y. Shiloh, L.C. Cantley, G.A. Rathbun, Utilization of oriented peptide libraries to identify substrate motifs selected by ATM, J Biol Chem 275 (2000) 22719-22727.
[15]J. Li, G.I. Lee, S.R. Van Doren, J.C. Walker, The FHA domain mediates phosphoprotein interactions, J Cell Sci 113 (Pt 23) (2000) 4143-4149.
[16]S. Matsuoka, G. Rotman, A. Ogawa, Y. Shiloh, K. Tamai, S.J. Elledge, Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro, Proc Natl Acad Sci USA 97 (2000) 10389-10394.
[17]Matsuoka, S., Nakagawa, T., Masuda, A., Haruki, N., Elledge, S.J. and Takahashi, T. (2001) Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res.,61,5362-5365.
[18]Cybulski, C., Gorski, B., Huzarski, T., Masojc, B., Mierzejewski, M., Debniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., Zlowocka, E., Lenner, M., Grabowska, E., Nej, K., Castaneda, J., Medrek, K., Szymanska, A., Szymanska, J., Kurzawski, G., Suchy, J., Oszurek, O., Witek, A., Narod, S.A. and Lubinski, J. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet.,75,1131-1135.
[19]Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J.M., McDonnell, S.K., Qian, C., Marks, A.F., Slager, S.L., Peterson, B.J., Smith, D.I., Cheville, J.C., Blute, M.L., Jacobsen, S.J., Schaid, D.J., Tindall, D.J., Thibodeau, S.N. and Liu, W. (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72,270-280.
[20]Lipton, L., Fleischmann, C., Sieber, O.M., Thomas, H.J., Hodgson, S.V., Tomlinson, I.P. and Houlston, R.S. (2003) Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett.,200,149-152.
[21]54] T. O'Neill, L. Giarratani, P. Chen, L. Iyer, C.H. Lee, M. Bobiak, F. Kanai, B.B. Zhou, J.H. Chung, G.A. Rathbun. (2002) Determination of Substrate Motifs for Human Chkl and hCdsl/Chk2 by the Oriented Peptide Library Approach, J Biol Chem.,277,16102-16115.
[22]G.J. Seo, S.E. Kim, Y.M. Lee, J.W. Lee, J.R. Lee, M.J. Hahn, S.T. Kim. (2003) Determination of substrate specificity and putative substrates of Chk2 kinase, Biochem Biophys Res Commun.,304,339-343.
[23]Bell, D.W., Varley, J.M., Szydlo, T.E., Kang, D.H., Wahrer, D.C., Shannon, K.E., Lubratovich, M., Verselis, S.J., Isselbacher, K.J., Fraumeni, J.F., Birch, J.M., Li, F.P., Garber, J.E. and Haber, D.A. (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science,286,2528-2531.
[24]Meijers-Heijboer, H., van den Ouweland, A., Klijn, J., Wasielewski, M., de Snoo, A., Oldenburg, R., Hollestelle, A., Houben, M., Crepin, E., van Veghel-Plandsoen, M., Elstrodt, F., van Duijn, C., Bartels, C., Meijers, C., Schutte, M., McGuffog, L. Thompson, D., Easton, D., Sodha, N., Seal, S., Barfoot, R., Mangion, J., Chang-Claude, J., Eccles, D., Eeles, R., Evans, D.G., Houlston, R., Murday, V., Narod, S., Peretz, T., Peto, J., Phelan, C., Zhang, H.X., Szabo, C., Devilee, P., Goldgar, D., Futreal, P.A., Nathanson, K.L., Weber, B., Rahman, N. and Stratton, M.R. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet.,31,55-59.
[25]Vahteristo, P., Bartkova, J., Eerola, H., Syrjakoski, K., Ojala, S., Kilpivaara, O., Tamminen, A., Kononen, J., Aittomaki, K., Heikkila, P., Holli, K., Blomqvist, C., Bartek, J., Kallioniemi, O.P. and Nevanlinna, H. (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet.,71, 432-438.
[26]Driver, K.E., Song, H., Lesueur, F., Ahmed, S., Barbosa-Morais, N.L., Tyrer, J.P., Ponder, B.A., Easton, D.F., Pharoah, P.D. and Dunning, A.M. (2008) Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis,29,333-341.
[27]Bahassi el, M., Penner, C.G., Robbins, S.B., Tichy, E., Feliciano, E., Yin, M., Liang, L., Deng, L., Tischfield, J.A. and Stambrook, P.J. (2007) The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model. Mutat. Res.,616,201-209.
[28]Matsuoka, S., Nakagawa, T., Masuda, A., Haruki, N., Elledge, S.J. and Takahashi, T. (2001) Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res.,61,5362-5365.
[29]Cybulski, C., Gorski, B., Huzarski, T., Masojc, B., Mierzejewski, M., Debniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., Zlowocka, E., Lenner, M., Grabowska, E., Nej, K., Castaneda, J., Medrek, K., Szymanska, A., Szymanska, J., Kurzawski, G., Suchy, J., Oszurek, O., Witek, A., Narod, S.A. and Lubinski, J. (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet.,75,1131-1135.
[30]Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J.M., McDonnell, S.K., Qian, C., Marks, A.F., Slager, S.L., Peterson, B.J., Smith, D.I., Cheville, J.C., Blute, M.L., Jacobsen, S.J., Schaid, D.J., Tindall, D.J., Thibodeau, S.N. and Liu, W. (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72,270-280.
[31]Lipton, L., Fleischmann, C., Sieber, O.M., Thomas, H.J., Hodgson, S.V., Tomlinson, I.P. and Houlston, R.S. (2003) Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett.,200,149-152.
[32]Hangaishi, A., Ogawa, S., Qiao, Y., Wang, L., Hosoya, N., Yuji, K., Imai, Y., Takeuchi, K., Miyawaki, S. and Hirai, H. (2002) Mutations of Chk2 in primary hematopoietic neoplasms. Blood,99,3075-3077.
[33]Hofmann, W.K., Miller, C.W., Tsukasaki, K., Tavor, S., Ikezoe, T., Hoelzer, D., Takeuchi, S. and Koeffler, H.P. (2001) Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. Leuk Res,25,333-338.
[34]Miller, C.W., Ikezoe, T., Krug, U., Hofmann, W.K., Tavor, S., Vegesna, V., Tsukasaki, K., Takeuchi, S. and Koeffler, H.P. (2002) Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosomes Cancer,33,17-21.
[35]Su, Y., Han, W., Giraldo, C., De Li, Y. and Block, E. R. (1998). Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am. J Respir. Cell Mol. Biol.,19,819-825.
[36]Grunau, C., Clark, S. J. and Rosenthal, A. (2001). Bisulfite genomic sequencing: systematic investigation of critical experimental parameters. Nucleic Acids Res.,29, E65-5.
[37]Walsh, T., Casadei, S., Coats, K.H., Swisher, E., Stray, S.M., Higgins, J., Roach, K.C., Mandell, J., Lee, M.K., Ciernikova, S., Foretova, L., Soucek, P. and King, M.C. (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Jama,295,1379-1388.
[38]Kilpivaara, O., Vahteristo, P., Falck, J., Syrjakoski, K., Eerola, H., Easton, D., Bartkova, J., Lukas, J., Heikkila, P., Aittomaki, K., Holli, K., Blomqvist, C., Kallioniemi, O.P., Bartek, J. and Nevanlinna, H. (2004) CHEK2 variant Ⅰ157T may be associated with increased breast cancer risk. Int J Cancer,111,543-537.
[39]Kleibl, Z., Havranek,O., Hlavata, I., Novotny, J., Sevcik, J., Pohlreich, P. and Soucek, P. (2009) The CHEK2 gene Ⅰ157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eu.r J. Cancer.,45,618-624.
[40]Brennan, P., McKay, J., Moore, L., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chow, W.H., Rothman, N., Chabrier, A., Gaborieau, V., Odefrey, F., Southey, M., Hashibe, M., Hall, J., Boffetta, P., Peto, J., Peto, R. and Hung, R.J. (2007) Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers:case control study. Hum. Mol. Genet.,16,1794-1801.
[41]Cybulski, C., Masojc, B., Oszutowska, D., Jaworowska, E., Grodzki, T. Waloszczyk, P., Serwatowski, P., Pankowski, J., Huzarski, T., Byrski, T., Gorski, B., Jakubowska, A., Debniak, T., Wokolorczyk, D., Gronwald, J., Tarnowska, C., Serrano-Fernandez, P., Lubinski, J. and Narod, S.A. (2008) Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. Carcinogenesis,29,762-765.
[42]Williams, L.H., Choong, D., Johnson, S.A. and Campbell, I.G. (2006) Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers. Clin. Cancer Res.,12,6967-6972.
[43]Zhang, P., Wang, J., Gao, W., Yuan, B.Z., Rogers, J. and Reed, E. (2004) CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer. Mol. Cancer,3,14.
[44]Wang, H., Wang, S., Shen, L., Chen, Y., Zhang, X., Zhou, J., Wang, Z., Hu, C., Yue, W. and Wang, H. (2009) Chk2 down-regulation by promoter hypermethylation in human bulk gliomas. Life Sci.
[45]Kim, D.S., Kim, M.J., Lee, J.Y., Lee, S.M., Choi, J.E., Lee, S.Y. and Park, J.Y. (2009) Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features. Lung Cancer,65,247-250.
[46]Zaid, A., Hodny, Z., Li, R. and Nelson, B.D. (2001) Spl acts as a repressor of the human adenine nucleotide translocase-2 (ANT2) promoter. Eur. J. Biochem.,268, 5497-5503.
[47]Ogra, Y., Suzuki, K., Gong, P., Otsuka, F. and Koizumi, S. (2001) Negative regulatory role of Spl in metal responsive element-mediated transcriptional activation. J. Biol. Chem.,276,16534-1659.
[48]Won, J., Yim, J. and Kim, T.K. (2002) Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. Faseb J.,16,1943-1945.
[49]Esteve, P.O., Chin, H.G. and Pradhan, S. (2007) Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J. Biol. Chem.,282,2615-2625.
[50]Clark, S.J., Harrison, J., Molloy, P.L. (1997)Spl binding is inhibited by (m)Cp(m)CpG methylation.Gene.195,67-71.
[1]Parkin,D.M., Bray,F., Ferlay,J., and Pisani,P. (2005) Global cancer statistics,2002. CA Cancer J Clin,55,74-108.
[2]邹小农.(2007)中国肺癌流行病学[J].中华肿瘤防治杂志.14(12)：881-883.
[3]Ezzati, M., Henley, S. J., Lopez, A. D., and Thun, M. J. (2005). Role of smoking in global and regional cancer epidemiology:current patterns and data needs. Int J Cancer 116,963-971.
[4]高国福,姚树祥,孙秀娣等.云南锡矿工肺癌的队列研究[J].中国肺癌杂志,2002,5(2)：81-91.
[5]李鲁,孙统达,张幸,等.单纯接触温石棉人员癌症死亡队列研究[J].中华预防医学杂志,2004,38(1)：39-42.
[6]Hoeijmakers, J. H. (2007). Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. Mech Ageing Dev 128,460-462.
[7]Umar, A., and Kunkel, T. A. (1996). DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem 238,297-307.
[8]Sonoda, E., Okada, T., Zhao, G. Y., Tateishi, S., Araki, K., Yamaizumi, M., Yagi, T., Verkaik, N. S., van Gent, D. C., Takata, M., and Takeda, S. (2003). Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. Embo J 22,3188-3197.
[9]Swaminathan S. (2004). Post-replication repair:ubiquitin throws the switch. Nat Cell Biol,6,578.
[10]Friedberg, E. C., Lehmann, A. R., and Fuchs, R. P. (2005). Trading places:how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18,499-505.
[11]Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., and Prakash, L. (2000). Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature 406, 1015-1019.
[12]Venkatesan, R. N., Bielas, J. H., and Loeb, L. A. (2006). Generation of mutator mutants during carcinogenesis. DNA Repair (Amst) 5,294-302.
[13]Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F., and Kunkel, T. A. (2000). Low fidelity DNA synthesis by human DNA polymerase-eta. Nature 404,1011-1013.
[14]Zhang, Y., Yuan, F., Wu, X., and Wang, Z. (2000). Preferential incorporation of G opposite template T by the low-fidelity human DNA polymerase iota. Mol Cell Biol 20, 7099-7108.
[15]Van Sloun, P. P., Varlet, I., Sonneveld, E., Boei, J. J., Romeijn, R. J., Eeken, J. C., and De Wind, N. (2002). Involvement of mouse Rev3 in tolerance of endogenous and exogenous DNA damage. Mol Cell Biol 22,2159-2169.
[16]Johnson R.E., Washington M.T., Haracska L., Prakash S., Prakash L.(2000b) Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions. Nature 406:1015-1019.
[17]Levine R.L., Miller H., Grollman A., Ohashi E., Ohmori H., Masutani C., Hanaoka F., Moriya M.(2001) Translesion DNA synthesis catalyzed by human Pol η and Pol κ across 1,N6-ethenodeoxyadenosine. J Biol Chem.276:18717-18721
[18]Alt, A., Lammens, K., Chiocchini, C., Lammens, A., Pieck, J. C., Kuch, D., Hopfner, K. P., and Carell, T. (2007). Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science 318,967-970.
[19]Lemontt, J. F. (1972). Induction of forward mutations in mutationally defective yeast. Mol Gen Genet 119,27-42.
[20]Andersen, P. L., Xu, F., and Xiao, W. (2008). Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA. Cell Res 18,162-173.
[21]Lin, W., Wu, X., and Wang, Z. (1999). A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. Mutat Res 433,89-98.
[22]Roos, W. P., Tsaalbi-Shtylik, A., Tsaryk, R., Guvercin, F., de Wind, N., and Kaina, B. (2009). The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Mol Pharmacol 76,927-934.
[23]Wang, X., Peterson, C. A., Zheng, H., Nairn, R. S., Legerski, R. J., and Li, L. (2001). Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol Cell Biol 21,713-720. [24] Nojima, K., Hochegger, H., Saberi, A., Fukushima, T., Kikuchi, K., Yoshimura, M., Orelli, B. J., Bishop, D. K., Hirano, S., Ohzeki, M., et al. (2005). Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65,11704-11711.
[25]Kawamura K., J O.W., Bahar R., Koshikawa N., Shishikura T., Nakagawara A., Sakiyama S., Kajiwara K., Kimura M. and Tagawa M. (2001). The error-prone DNA polymerase zeta catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues. Int J Oncol 18,97-103.
[26]Wittschieben, J. P., Reshmi, S. C., Gollin, S. M., and Wood, R. D. (2006). Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res 66,134-142.
[27]Bemark, M., Khamlichi, A. A., Davies, S. L., and Neuberger, M. S. (2000). Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr Biol 10,1213-1216.
[28]Esposito, G., Godindagger, I., Klein, U., Yaspo, M. L., Cumano, A., and Rajewsky, K. (2000). Disruption of the Rev31-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality. Curr Biol 10,1221-1224.
[29]Yu, Y., Yang, J., Zhu, F., and Xu, F. (2004). Response of REV3 promoter to N-methyl-N'-nitro-N-nitrosoguanidine. Mutat Res 550,49-58
[30]Zhu, F., Jin, C. X., Song, T., Yang, J., Guo, L., and Yu, Y. N. (2003). Response of human REV3 gene to gastric cancer inducing carcinogen N-methyl-N'-nitro-N-nitrosoguanidine and its role in mutagenesis. World J Gastroenterol 9,888-893.
[31]Brondello, J. M., Pillaire, M. J., Rodriguez, C., Gourraud, P. A., Selves, J., Cazaux, C., and Piette, J. (2008). Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 27,6093-6101.
[32]Pan, Q., Fang, Y., Xu, Y., Zhang, K., and Hu, X. (2005). Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett 217,139-147.
[33]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. (2002) The structure of haplotype blocks in the human genome. Science 296:2225-2229.
[34]Barrett JC, Fry B, Maller J, Daly MJ. (2005) Haploview:analysis and visualization of LD and haplotype maps. Bioinformatics 21:263-265.
[35]Schmid, W. (1975). The micronucleus test. Mutat Res 31,9-15.
[36]Lehmann, A. R. (2005). Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579,873-876.
[37]Prakash, S., and Prakash, L. (2002). Translesion DNA synthesis in eukaryotes:a one-or two-polymerase affair. Genes Dev 16,1872-1883.
[38]Gibbs, P. E., McGregor, W. G., Maher, V. M., Nisson, P., and Lawrence, C. W. (1998). A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 95,6876-6880.
[39]Lin, W., Wu, X., and Wang, Z. (1999). A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. Mutat Res 433,89-98.
[40]Rockwell, S., Yuan, J., Peretz, S., and Glazer, P. M. (2001). Genomic instability in cancer. Novartis Found Symp 240,133-142.
[41]Datta, A., and Jinks-Robertson, S. (1995). Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 268,1616-1619.
[42]Kajiwara, K., Kimura, M., and Tagawa, M. (2001). The error-prone DNA polymerase zeta catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues. Int J Oncol 18,97-103.
[43]Krieg, A. J., Hammond, E. M., and Giaccia, A. J. (2006). Functional analysis of p53 binding under differential stresses. Mol Cell Biol 26,7030-7045.
[44]Kim, V. N., and Nam, J. W. (2006). Genomics of microRNA. Trends Genet 22,165-173.
[45]Doench, J. G., and Sharp, P. A. (2004). Specificity of microRNA target selection in translational repression. Genes Dev 18,504-511.
[46]He, L., and Hannon, G. J. (2004). MicroRNAs:small RNAs with a big role in gene regulation. Nat Rev Genet 5,522-531.
[47]Calin, G. A., and Croce, C. M. (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6,857-866.
[48]Vatolin, S., Navaratne, K., and Weil, R. J. (2006). A novel method to detect functional microRNA targets. J Mol Biol 358,983-996.
[49]Saunders, M. A., Liang, H., and Li, W. H. (2007). Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104,3300-3305.
[50]Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibe, B., Bouix, J., Caiment, F., Elsen, J. M., Eychenne, F., et al. (2006). A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38,813-818.
[51]Wang, G., van der Walt, J. M., Mayhew, G., Li, Y. J., Zuchner, S., Scott, W. K., Martin, E. R., and Vance, J. M. (2008). Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 82,283-289.
[52]Mishra, P. J., Humeniuk, R., Mishra, P. J., Longo-Sorbello, G. S., Banerjee, D., and Bertino, J. R. (2007). A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 104,13513-13518
[1]Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. Nature 411,366-374.
[2]Umar, A., and Kunkel, T. A. (1996). DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem 238,297-307.
[3]Swaminathan S. (2004). Post-replication repair:ubiquitin throws the switch. Nat Cell Biol,6,578.
[4]Hubscher, U., Maga, G., Spadari, S. (2002) Eukaryotic DNA polymerases. Annu Rev Biochem 71,133-163.
[5]Friedberg, E. C., Lehmann, A. R., and Fuchs, R. P. (2005). Trading places:how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18,499-505.
[6]Lehmann, A. R. (2005). Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579,873-876.
[7]Gibbs, P. E., McGregor, W. G., Maher, V. M., Nisson, P., and Lawrence, C. W. (1998). A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 95,6876-6880.
[8]Friedberg, E. C., Wagner, R., and Radman, M. (2002). Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science 296,1627-1630.
[9]Sonoda, E., Okada, T., Zhao, G. Y., Tateishi, S., Araki, K., Yamaizumi, M., Yagi, T. Verkaik, N. S., van Gent, D. C., Takata, M., and Takeda, S. (2003). Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. Embo J 22,3188-3197.
[10]Gan, G. N., Wittschieben, J. P., Wittschieben, B. O., and Wood, R. D. (2008). DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 18,174-183.
[11]Lawrence, C. W., and Maher, V. M. (2001). Mutagenesis in eukaryotes dependent on DNA polymerase zeta and Revlp. Philos Trans R Soc Lond B Biol Sci 356,41-46.
[12]Lawrence, C. W. (2004). Cellular functions of DNA polymerase zeta and Revl protein. Adv. Protein Chem 69:167-203.
[13]Pan, Q., Fang, Y., Xu, Y., Zhang, K., and Hu, X. (2005). Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett 217,139-147.
[14]Wang, H. B., Zhang, S. Y., Wang, S., Lv, J., Wu, W. T., Weng, L., Chen, D., Zhang, Y., Lu, Z. P., Yang, J. M., et al. (2009). REV3L confers chemoresistance to cisplatin in human gliomas:The potential of its RNAi for synergistic therapy. Neuro Oncol.
[15]Brondello, J. M., Pillaire, M. J., Rodriguez, C., Gourraud, P. A., Selves, J., Cazaux, C., and Piette, J. (2008). Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 27,6093-6101.
[16]Bavoux, C., Hoffmann, J. S., and Cazaux, C. (2005). Adaptation to DNA damage and stimulation of genetic instability:the double-edged sword mammalian DNA polymerase kappa. Biochimie 87,637-646.
[17]Lemee, F., Bavoux, C., Pillaire, M. J., Bieth, A., Machado, C. R., Pena, S. D., Guimbaud, R., Selves, J., Hoffmann, J. S., and Cazaux, C. (2007). Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase kappa in colorectal cancer. Oncogene 26,3387-3394.
[18]Ogi, T., Kannouche, P., and Lehmann, A. R. (2005). Localisation of human Y-family DNA polymerase kappa:relationship to PCNA foci. J Cell Sci 118,129-136.
[19]Masutani, C., R. Kusumoto, A. Yamada, N. Dohmae, M. Yokoi, M. Yuasa, M. Araki, S. Iwai, K. Takio, and F. Hanaoka. (1999). The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 399:700-704.
[20]Abdulovic, A. L., and S. Jinks-Robertson. (2006). The in vivo characterization of translesion synthesis across UV-induced lesions in Saccharomyces cerevisiae:insights into Pol zeta-and Pol eta-dependent frameshift mutagenesis. Genetics 172,1487-1498.
[21]Kawamoto, T., K. Araki, E. Sonoda, Y. M. Yamashita, K. Harada, K. Kikuchi, C. Masutani, F. Hanaoka, K. Nozaki, N. Hashimoto, and S. Takeda. (2005). Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell 20,793-799.
[22]McCulloch, S. D., and T. A. Kunkel. (2008). The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 18:148-161.
[23]Nair, D. T., R. E. Johnson, S. Prakash, L. Prakash, and A. K. Aggarwal. (2004). Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature 430,377-380.
[24]Blanca, G., G. Villani, I. Shevelev, K. Ramadan, S. Spadari, U. Hubscher,and G. Maga. (2004). Human DNA polymerases lambda and beta show different efficiencies of translesion DNA synthesis past abasic sites and alternative mechanisms for frameshift generation. Biochemistry 43,11605-11615.
[25]Moon, A. F., M. Garcia-Diaz, V. K. Batra, W. A. Beard, K. Bebenek, T. A. Kunkel, S. H. Wilson, and L. C. Pedersen. (2007). The X family portrait:structural insights into biological functions of X family polymerases. DNA Repair (Amsterdam) 6,1709-1725.
[26]Prakash, S., and Prakash, L. (2002). Translesion DNA synthesis in eukaryotes:a one-or two-polymerase affair. Genes Dev 16,1872-1883.
[27]Vandewiele, D., Borden, A., O'Grady, P. I., Woodgate, R., and Lawrence, C. W. (1998). Efficient translesion replication in the absence of Escherichia coli Umu proteins and 3'-5'exonuclease proofreading function. Proc Natl Acad Sci USA 95,15519-15524.
[28]Kunz, B. A., Ramachandran, K., and Vonarx, E. J. (1998). DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae. Genetics 148,1491-1505.
[29]Wittschieben, J. P., Reshmi, S. C., Gollin, S. M., and Wood, R. D. (2006). Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res 66,134-142.
[30]Bemark, M., Khamlichi, A. A., Davies, S. L., and Neuberger, M. S. (2000). Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr Biol 10,1213-1216.
[31]Wang, X., Peterson, C. A., Zheng, H., Nairn, R. S., Legerski, R. J., and Li, L. (2001). Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol Cell Biol 21,713-720.
[32]Wood, R. D., Mitchell, M., Sgouros, J., and Lindahl, T. (2001). Human DNA repair genes. Science 291,1284-1289.
[33]Nojima, K., Hochegger, H., Saberi, A., Fukushima, T., Kikuchi, K., Yoshimura, M., Orelli, B. J., Bishop, D. K., Hirano, S., Ohzeki, M., et al. (2005). Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65,11704-11711.
[34]Shen, X., Jun, S., O'Neal, L. E., Sonoda, E., Bemark, M., Sale, J. E., and Li, L (2006). REV3 and REV1 play major roles in recombination-independent repair of DNA interstrand cross-links mediated by monoubiquitinated proliferating cell nuclear antigen (PCNA). J Biol Chem 281,13869-13872.
[35]Wu, F., Lin, X., Okuda, T., and Howell, S. B. (2004). DNA polymerase zeta regulates cisplatin cytotoxicity, mutagenicity, and the rate of development of cisplatin resistance. Cancer Res 64,8029-8035.
[36]Albertella, M. R., Green, C. M., Lehmann, A. R., and O'Connor, M. J. (2005). A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res 65, 9799-9806.
[37]Lin, X., Trang, J., Okuda, T., and Howell, S. B. (2006). DNA polymerase zeta accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost DNA mismatch repair. Clin Cancer Res 12,563-568.
[38]Okuda, T., Lin, X., Trang, J., and Howell, S. B. (2005). Suppression of hREV1 expression reduces the rate at which human ovarian carcinoma cells acquire resistance to cisplatin. Mol Pharmacol 67,1852-1860.
[39]Cheung, H. W., Chun, A. C., Wang, Q., Deng, W., Hu, L., Guan, X. Y., Nicholls, J. M., Ling, M. T., Chuan Wong, Y., Tsao, S. W., et al. (2006). Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer Res 66,4357-4367.
[40]Roos, W. P., Tsaalbi-Shtylik, A., Tsaryk, R., Guvercin, F., de Wind, N., and Kaina, B. (2009). The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Mol Pharmacol 76,927-934.