丙型肝炎病毒非结构蛋白5B与细胞蛋白CINP相互作用影响细胞周期及其机制的研究
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摘要
丙型肝炎病毒(Hepatitis C Virus, HCV)感染后通常在体内保持低水平复制,但却极易引起慢性肝炎、肝硬化甚至肝癌,具体机制至今尚不是很清楚。已知细胞周期的紊乱是肿瘤细胞发生的关键环节,一些与肿瘤发生相关的病毒感染均可引起细胞周期的紊乱。HCV是单正链RNA病毒,其基因组可编码包括结构蛋白和非结构蛋白在内的至少10种病毒蛋白。其中NS5B是HCV编码的非结构蛋白之一,具有RNA依赖的RNA多聚酶活性,是HCV复制的关键酶。近来有报道称NS5B除直接参与HCV复制外,还可以通过与宿主因子的相互作用影响正常细胞功能,例如免疫反应及细胞周期等,从而引起病变发生。已有报道提示NS5B蛋白可影响细胞周期进展,但不同研究小组所观察到的现象不太一致,且详细机制还不是很清楚。
为确认NS5B对细胞周期的影响,首先在肝癌细胞系HepG2中构建了可由四环素调控的NS5B稳定表达细胞株(HepG2 Tet-on NS5B)。经G418和hygromycin B共同筛选,最终得到低背景高诱导表达的细胞克隆。Dox (doxycycline)诱导后,NS5B可被标签抗体和内源性抗体同时检测到,提示细胞系构建成功。然后利用流式细胞术在该细胞系中检测NS5B对细胞周期的影响。结果显示,NS5B诱导表达后,S期细胞明显增多,提示NS5B可使细胞周期S期延长。
为探讨NS5B影响细胞周期的分子机制,包括何种宿主蛋白参与该过程,应用酵母双杂交试验从肝细胞文库中筛选了可能与NS5B存在相互作用的细胞蛋白,发现细胞蛋白CINP (cyclin-dependent kinase 2 (CDK2)-interacting protein)为候选蛋白之一。鉴于CINP跟细胞周期相关,可以推测NS5B可能通过与CINP的相互作用影响了细胞周期。为了验证这一假设,利用GST pull-down和免疫共沉淀证实NS5B与CINP之间的相互作用,免疫荧光激光共聚焦试验也观察到两者在胞浆核周区域存在部分共定位。截短体试验进一步表明两者之间的相互作用,且发现CINP的C末端负责与NS5B相互作用,而NS5B的84-95及455464两段氨基酸负责与CINP相互作用。
CINP最早是在HeLa细胞中以CDK2相互作用蛋白被发现,前期研究表明CINP可与染色体结合,参与DNA的合成。为了确认CINP是否具有对细胞周期的调控功能,用胸腺嘧啶核苷使HeLa细胞同步化于细胞周期的G1/S期,再转染CINP及相应空载体,流式检测细胞周期变化。结果发现空载体转染组可进入正常细胞周期,而CINP转染组细胞仍停滞在G1期。用小干扰RNA将内源性CINP干扰后,S期细胞显著增多。这些结果提示CINP确实存在对细胞周期的调控功能。接着将不能与CINP相互作用的NS5B截短突变体(ANS5B)与全长NS5B或相应空载体分别转入细胞,流式细胞术和CCK-8检测结果发现：与全长NS5B相比,ΔNS5B和空载体转染组细胞周期和细胞生长均不受影响,提示NS5B对细胞周期的影响依赖其与CINP的结合。
为了进一步探讨NS5B与CINP相互作用之后影响细胞周期的分子机制,首先检测NS5B对CINP的蛋白表达是否有影响。结果发现不同情况下NS5B的表达对CINP的蛋白水平都没有明显改变。由于CINP是胞核蛋白,而NS5B主要定位于胞浆,先前的共聚焦结果显示两者可在核周区域部分共定位,提示NS5B可能使CINP发生了亚细胞定位的改变。激光共聚焦试验验证了这个假设：全长NS5B可使原本在核内的CINP重新定位于胞浆,而不与CINP结合的截短体△NS5B则不具备这个功能。同时,在HCV亚基因组复制子和细胞培养病毒JFH-1感染的Huh7.5细胞中也可观察到CINP定位的改变。除此之外,核浆分离的结果也发现CINP在NS5B表达的细胞中发生从核到浆的移位；将JFH-1感染后的Huh7.5细胞持续传代来模拟慢性感染过程,也得到类似的结果。
DNA损伤反应(DNA damage response, DDR)是DNA损伤发生时调控细胞周期的重要信号通路。DNA损伤发生后,有三个细胞周期检查点可被激活：G1/S期阻止细胞进入S期；intra-S期抑制DNA合成；G2/M期防止损伤的DNA继续分裂。近期有报道显示CINP也可参与DNA损伤反应通路并具有维持基因组稳定性的作用,提示DDR可能介导了NS5B/CINP相互作用后细胞周期的紊乱。因为NS5B使CINP从核到浆的移位减少了核内发挥功能的CINP的量,用RNA干扰直接下调CINP后发现DDR通路中的可对S期进行调控的重要分子pRb、pChk1显著降低而p21则明显升高。与此相一致,NS5B诱导表达后pRb、pChk1也有明显下调且可被CINP的过表达所部分回复。这些结果提示NS5B可能通过与CINP相互作用影响了DDR通路进而对细胞周期产生影响。
上述结果表明,HCV NS5B与CINP的相互作用可使CINP发生从胞核到胞浆的移位,从而影响了DDR通路,使细胞S期延长。这为深入了解HCV持续性感染和肿瘤发生的机制开辟了新的思路。
Hepatitis C virus always keep low level replication after infection, However, it is easily develops into a chronic infection, liver cirrhosis and ultimately hepatocellular carcinoma, the molecular mechanisms have thus far remained unclear. Cell cycle dysregulation is a critical event in virus infection-associated tumorigenesis. HCV non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) and plays an essential role in HCV RNA replication. Recently, there is increasing experimental evidence supporting the possibility that the direct interaction of NS5B with host factors results in a series of cellular activities, such as cell cycle progression, host immune responses and so on. There have also been investigations suggesting that NS5B is involved in cell cycle regulation. However, there is still controversy around this phenomenon and confusion about the details of the mechanism.
To determine the effect of NS5B on cell cycle progression in hepatocyte-derived cells, a HepG2 Tet-on NS5B stable cell line was established. The success establishment was confirmed by western blotting with both anti tag antibody and anti endogenous NS5B antibody. Then, this cell line was employed to study the effect of NS5B on cell cycle. The result showed that the induction of NS5B lead to obviously S-phase accumulation.
Our previous study indicated that the cellular protein CINP which interact with NS5B is closely associated with cell cycle, suggesting NS5B might affect cell cycle through interacting with CINP. Firstly, GST pull-down and co-IP assay was performed to confirmed the association of NS5B with CINP, Immunofluorescence assay also observed their partially colocalization in the perinuclear region. The further protein truncation assay was performed to map the amino acid sequences required for their binding with each other. And results demonstrated that the C-terminal end of CINP and two NS5B sequences (aa 84-95 and 455-464) are required for their binding.
CINP was identified as CDK2-interacting protein from a HeLa cDNA expression library. Previously report showed that CINP is associated with chromosome and involve in the initiation of DNA replication. To determine whether CINP has the function to regulate cell cycle progression, HeLa cells were synchronized with thymidine (TdR) in the G1/S transition phase and then transfection with CINP or related empty vectors. Following release, cells transfected with empty vectors were able to resume a normal cell cycle progression. However, cells transfected with CINP were still in G1/S phase. Knockdown CINP with specific siRNA resulted in an obvious S-phase accumulation, which indicates the importance of CINP in host cell cycle regulation, further results came from the NS5B deletion mutant (96-454,△NS5B) that failed to bind CINP has no effect on cell cycle and cell proliferation suggested that the CINP/NS5B association is required for cell cycle delay.
CINP has been found to localize to the nucleus, whereas NS5B primarily localizes to the perinuclear region. Our above data showed a perinuclear colocalization of NS5B with CINP, which suggests that NS5B caused the relocalization of CINP from the nucleus to the cytoplasm. To test this hypothesis, GFP-CINP was co-transfected with empty vector, myc-NS5B or myc-△NS5B into Huh7 cells, and cells were analyzed by confocal microscopy after immunological staining with an anti-myc antibody. Strong merged signals were observed in the perinuclear regions in GFP-CINP and full-length NS5B co-transfected cells. However, most CINP remained localized to the nucleus in empty vector- and△NS5B-transfected cells. The HCV subgenomic replicon and JFH-1-infected cells exhibit the similar results. The relocalization of CINP by NS5B was also confirmed by the next extraction of a subcellular fractionation assay.
The DNA damage response (DDR) is usually employed by viruses or virus-encoded proteins to modulate the cell cycle to promote their own replication and oncogenic effects. After DNA damage, three cell cycle checkpoints are activated:1) The G1/S checkpoint prevents cells from entering S-phase; 2) The intra-S-phase checkpoint inhibits DNA replication; and 3) The G2/M checkpoint prevents damaged DNA from undergoing mitosis. Recent study identified CINP as a checkpoint protein to maintain genomic stability, thus shedding light on the function of CINP in genomic maintenance and cell cycle regulation. Because CINP translocation by NS5B reduced the amount of CINP available for normal cellular regulation in the nucleus, there might be an alteration of signaling pathways that involve CINP. Directly knocking down CINP by specific siRNA resulted in a significant alteration of DNA damage response and cell cycle checkpoint proteins, such as an increase in p21, a decrease in pRb and pChkl. Similar results were also observed in cells with NS5B present and could be partially restored by the ectopic overexpression of CINP. And after knocking down Chkl with specific siRNA could also lead to S-phase accumulation, which suggested that the DNA damage response might be exploited by NS5B to modify cell cycle progression.
Taken together, our data demonstrate that NS5B delays S-phase progression through interacting and relocalizing CINP from the nucleus to the cytoplasm, which provides new insights into understanding persistence and tumorigenesis after HCV infection.
为确认NS5B对细胞周期的影响,首先在肝癌细胞系HepG2中构建了可由四环素调控的NS5B稳定表达细胞株(HepG2 Tet-on NS5B)。经G418和hygromycin B共同筛选,最终得到低背景高诱导表达的细胞克隆。Dox (doxycycline)诱导后,NS5B可被标签抗体和内源性抗体同时检测到,提示细胞系构建成功。然后利用流式细胞术在该细胞系中检测NS5B对细胞周期的影响。结果显示,NS5B诱导表达后,S期细胞明显增多,提示NS5B可使细胞周期S期延长。
为探讨NS5B影响细胞周期的分子机制,包括何种宿主蛋白参与该过程,应用酵母双杂交试验从肝细胞文库中筛选了可能与NS5B存在相互作用的细胞蛋白,发现细胞蛋白CINP (cyclin-dependent kinase 2 (CDK2)-interacting protein)为候选蛋白之一。鉴于CINP跟细胞周期相关,可以推测NS5B可能通过与CINP的相互作用影响了细胞周期。为了验证这一假设,利用GST pull-down和免疫共沉淀证实NS5B与CINP之间的相互作用,免疫荧光激光共聚焦试验也观察到两者在胞浆核周区域存在部分共定位。截短体试验进一步表明两者之间的相互作用,且发现CINP的C末端负责与NS5B相互作用,而NS5B的84-95及455464两段氨基酸负责与CINP相互作用。
CINP最早是在HeLa细胞中以CDK2相互作用蛋白被发现,前期研究表明CINP可与染色体结合,参与DNA的合成。为了确认CINP是否具有对细胞周期的调控功能,用胸腺嘧啶核苷使HeLa细胞同步化于细胞周期的G1/S期,再转染CINP及相应空载体,流式检测细胞周期变化。结果发现空载体转染组可进入正常细胞周期,而CINP转染组细胞仍停滞在G1期。用小干扰RNA将内源性CINP干扰后,S期细胞显著增多。这些结果提示CINP确实存在对细胞周期的调控功能。接着将不能与CINP相互作用的NS5B截短突变体(ANS5B)与全长NS5B或相应空载体分别转入细胞,流式细胞术和CCK-8检测结果发现：与全长NS5B相比,ΔNS5B和空载体转染组细胞周期和细胞生长均不受影响,提示NS5B对细胞周期的影响依赖其与CINP的结合。
为了进一步探讨NS5B与CINP相互作用之后影响细胞周期的分子机制,首先检测NS5B对CINP的蛋白表达是否有影响。结果发现不同情况下NS5B的表达对CINP的蛋白水平都没有明显改变。由于CINP是胞核蛋白,而NS5B主要定位于胞浆,先前的共聚焦结果显示两者可在核周区域部分共定位,提示NS5B可能使CINP发生了亚细胞定位的改变。激光共聚焦试验验证了这个假设：全长NS5B可使原本在核内的CINP重新定位于胞浆,而不与CINP结合的截短体△NS5B则不具备这个功能。同时,在HCV亚基因组复制子和细胞培养病毒JFH-1感染的Huh7.5细胞中也可观察到CINP定位的改变。除此之外,核浆分离的结果也发现CINP在NS5B表达的细胞中发生从核到浆的移位；将JFH-1感染后的Huh7.5细胞持续传代来模拟慢性感染过程,也得到类似的结果。
DNA损伤反应(DNA damage response, DDR)是DNA损伤发生时调控细胞周期的重要信号通路。DNA损伤发生后,有三个细胞周期检查点可被激活：G1/S期阻止细胞进入S期；intra-S期抑制DNA合成；G2/M期防止损伤的DNA继续分裂。近期有报道显示CINP也可参与DNA损伤反应通路并具有维持基因组稳定性的作用,提示DDR可能介导了NS5B/CINP相互作用后细胞周期的紊乱。因为NS5B使CINP从核到浆的移位减少了核内发挥功能的CINP的量,用RNA干扰直接下调CINP后发现DDR通路中的可对S期进行调控的重要分子pRb、pChk1显著降低而p21则明显升高。与此相一致,NS5B诱导表达后pRb、pChk1也有明显下调且可被CINP的过表达所部分回复。这些结果提示NS5B可能通过与CINP相互作用影响了DDR通路进而对细胞周期产生影响。
上述结果表明,HCV NS5B与CINP的相互作用可使CINP发生从胞核到胞浆的移位,从而影响了DDR通路,使细胞S期延长。这为深入了解HCV持续性感染和肿瘤发生的机制开辟了新的思路。
Hepatitis C virus always keep low level replication after infection, However, it is easily develops into a chronic infection, liver cirrhosis and ultimately hepatocellular carcinoma, the molecular mechanisms have thus far remained unclear. Cell cycle dysregulation is a critical event in virus infection-associated tumorigenesis. HCV non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) and plays an essential role in HCV RNA replication. Recently, there is increasing experimental evidence supporting the possibility that the direct interaction of NS5B with host factors results in a series of cellular activities, such as cell cycle progression, host immune responses and so on. There have also been investigations suggesting that NS5B is involved in cell cycle regulation. However, there is still controversy around this phenomenon and confusion about the details of the mechanism.
To determine the effect of NS5B on cell cycle progression in hepatocyte-derived cells, a HepG2 Tet-on NS5B stable cell line was established. The success establishment was confirmed by western blotting with both anti tag antibody and anti endogenous NS5B antibody. Then, this cell line was employed to study the effect of NS5B on cell cycle. The result showed that the induction of NS5B lead to obviously S-phase accumulation.
Our previous study indicated that the cellular protein CINP which interact with NS5B is closely associated with cell cycle, suggesting NS5B might affect cell cycle through interacting with CINP. Firstly, GST pull-down and co-IP assay was performed to confirmed the association of NS5B with CINP, Immunofluorescence assay also observed their partially colocalization in the perinuclear region. The further protein truncation assay was performed to map the amino acid sequences required for their binding with each other. And results demonstrated that the C-terminal end of CINP and two NS5B sequences (aa 84-95 and 455-464) are required for their binding.
CINP was identified as CDK2-interacting protein from a HeLa cDNA expression library. Previously report showed that CINP is associated with chromosome and involve in the initiation of DNA replication. To determine whether CINP has the function to regulate cell cycle progression, HeLa cells were synchronized with thymidine (TdR) in the G1/S transition phase and then transfection with CINP or related empty vectors. Following release, cells transfected with empty vectors were able to resume a normal cell cycle progression. However, cells transfected with CINP were still in G1/S phase. Knockdown CINP with specific siRNA resulted in an obvious S-phase accumulation, which indicates the importance of CINP in host cell cycle regulation, further results came from the NS5B deletion mutant (96-454,△NS5B) that failed to bind CINP has no effect on cell cycle and cell proliferation suggested that the CINP/NS5B association is required for cell cycle delay.
CINP has been found to localize to the nucleus, whereas NS5B primarily localizes to the perinuclear region. Our above data showed a perinuclear colocalization of NS5B with CINP, which suggests that NS5B caused the relocalization of CINP from the nucleus to the cytoplasm. To test this hypothesis, GFP-CINP was co-transfected with empty vector, myc-NS5B or myc-△NS5B into Huh7 cells, and cells were analyzed by confocal microscopy after immunological staining with an anti-myc antibody. Strong merged signals were observed in the perinuclear regions in GFP-CINP and full-length NS5B co-transfected cells. However, most CINP remained localized to the nucleus in empty vector- and△NS5B-transfected cells. The HCV subgenomic replicon and JFH-1-infected cells exhibit the similar results. The relocalization of CINP by NS5B was also confirmed by the next extraction of a subcellular fractionation assay.
The DNA damage response (DDR) is usually employed by viruses or virus-encoded proteins to modulate the cell cycle to promote their own replication and oncogenic effects. After DNA damage, three cell cycle checkpoints are activated:1) The G1/S checkpoint prevents cells from entering S-phase; 2) The intra-S-phase checkpoint inhibits DNA replication; and 3) The G2/M checkpoint prevents damaged DNA from undergoing mitosis. Recent study identified CINP as a checkpoint protein to maintain genomic stability, thus shedding light on the function of CINP in genomic maintenance and cell cycle regulation. Because CINP translocation by NS5B reduced the amount of CINP available for normal cellular regulation in the nucleus, there might be an alteration of signaling pathways that involve CINP. Directly knocking down CINP by specific siRNA resulted in a significant alteration of DNA damage response and cell cycle checkpoint proteins, such as an increase in p21, a decrease in pRb and pChkl. Similar results were also observed in cells with NS5B present and could be partially restored by the ectopic overexpression of CINP. And after knocking down Chkl with specific siRNA could also lead to S-phase accumulation, which suggested that the DNA damage response might be exploited by NS5B to modify cell cycle progression.
Taken together, our data demonstrate that NS5B delays S-phase progression through interacting and relocalizing CINP from the nucleus to the cytoplasm, which provides new insights into understanding persistence and tumorigenesis after HCV infection.
引文
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21. van Ham T, Foijer F, van Vugt M, Banerjee R, Yang F, Oostra A, Joenje H, te Riele H:Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 2010,24:1377-1388.
22. Srinivasan SV, Mayhew CN, Schwemberger S, Zagorski W, Knudsen ES:RB loss promotes aberrant ploidy by deregulating levels and activity of DNA replication factors. JBiol Chem 2007,282:23867-23877.
23. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z, Mert O, Dickins RA, Narita M, Zhang M, Lowe SW:Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 2010,17:376-387.
24. Lovejoy CA, Xu X, Bansbach CE, Glick GG, Zhao RX, Ye F, Sirbu BM, Titus LC, Shyr Y, Cortez D:Functional genomic screens identify CINP as a genome maintenance protein. Proceedings of the National Academy of Sciences of the United States of America 2009,106:19304-19309.
25. Munakata T, Liang Y, Kim S, McGivern DR, Huibregtse J, Nomoto A, Lemon SM:Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein. PLoS Pathog 2007,3:1335-1347.
26. McGivern DR, Villanueva RA, Chinnaswamy S, Kao CC, Lemon SM: Impaired replication of hepatitis C virus containing mutations in a conserved NS5B retinoblastoma protein-binding motif. J Virol 2009, 83:7422-7433.
27. Vannucchi S, Percario ZA, Chiantore MV, Matarrese P, Chelbi-Alix MK, Fagioli M, Pelicci PG, Malorni W, Fiorucci G, Romeo G, Affabris E: Interferon-beta induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells. Oncogene 2000,19:5041-5053.
28. Harper JW, Elledge SJ:The DNA damage response:ten years after. Mol Cell 2007,28:739-745.
29. Jackson SP, Bartek J:The DNA-damage response in human biology and disease. Nature 2009,461:1071-1078.
30. Shiloh Y:ATM and related protein kinases:safeguarding genome integrity. Nat Rev Cancer 2003,3:155-168.
31. Guo Z, Kumagai A, Wang SX, Dunphy WG:Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev 2000,14:2745-2756.
32. Lopez-Girona A, Tanaka K, Chen XB, Baber BA, McGowan CH, Russell P: Serine-345 is required for Rad3-dependent phosphorylation and function of checkpoint kinase Chkl in fission yeast. Proceedings of the National Academy of Sciences of the United States of America 2001,98:11289-11294.
33. Melchionna R, Chen XB, Blasina A, McGowan CH:Threonine 68 is required for radiation-induced phosphorylation and activation of Cdsl. Nature Cell Biology 2000,2:762-765.
34. Aressy B, Ducommun B:Cell Cycle Control by the CDC25 Phosphatases. Anti-Cancer Agents in Medicinal Chemistry 2008,8:818-824.
35. Haugwitz U, Wiedmann M, Spiesbach K, Engeland K, Mossner J:Regulation of genes for the cdc25 phosphatases is important for checkpoint control during the cell division cycle. Gastroenterology 2001,120:A501-A501.
36. Grishina I, Lattes B:A novel Cdk2 interactor is phosphorylated by Cdc7 and associates with components of the replication complexes. Cell Cycle 2005,4:1120-1126.
37. Miller LD, Park KS, Guo QM, Alkharouf NW, Malek RL, Lee NH, Liu ET, Cheng SY:Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation. Mol Cell Biol 2001,21:6626-6639.
38. Jakobs A, Himstedt F, Funk M, Korn B, Gaestel M, Niedenthal R:Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation. Nucleic Acids Res 2007,35:e109.
39. Paulsen RD, Soni DV, Wollman R, Hahn AT, Yee MC, Guan A, Hesley JA, Miller SC, Cromwell EF, Solow-Cordero DE, et al:A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability. Mol Cell 2009,35:228-239.
40. Grossman WJ, Kimata JT, Wong FH, Zutter M, Ley TJ, Ratner L: Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type Ⅰ. Proc Natl Acad Sci USA 1995,92:1057-1061.
41. Kudoh A, Fujita M, Zhang LM, Shirata N, Daikoku T, Sugaya Y, Isomura H, Nishiyama Y, Tsurumi T:Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. Journal of Biological Chemistry 2005,280:8156-8163.
42. Radkov SA, Kellam P, Boshoff C:The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med 2000, 6:1121-1127.
43. Choi BH, Choi M, Jeon HY, Rho HM:Hepatitis B viral X protein overcomes inhibition of E2F1 activity by pRb on the human Rb gene promoter. DNA Cell Biol 2001,20:75-80.
44. Harrington EA, Bruce JL, Harlow E, Dyson N:pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc Natl Acad Sci U S A 1998, 95:11945-11950.
45. Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES:RB-dependent S-phase response to DNA damage. Mol Cell Biol 2000,20:7751-7763.
46. Zhu Y, Alvarez C, Doll R, Kurata H, Schebye XM, Parry D, Lees E: Intra-S-phase checkpoint activation by direct CDK2 inhibition. Mol Cell Biol 2004,24:6268-6277.
47. Zhao H, Piwnica-Worms H:ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 2001, 21:4129-4139.
48. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H: Chkl mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem 2003,278:21767-21773.
49. Hu B, Zhou XY, Wang X, Zeng ZC, Iliakis G, Wang Y:The radioresistance to killing of Al-5 cells derives from activation of the Chkl pathway. J Biol Chem 2001,276:17693-17698.
50. Zou L, Elledge SJ:Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 2003,300:1542-1548.
51. Jirmanova L, Bulavin DV, Fornace AJ, Jr.:Inhibition of the ATR/Chkl pathway induces a p38-dependent S-phase delay in mouse embryonic stem cells. Cell Cycle 2005,4:1428-1434.
52. Shimada M, Niida H, Zineldeen DH, Tagami H, Tanaka M, Saito H, Nakanishi M:Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 2008,132:221-232.
53. Naruyama H, Shimada M, Niida H, Zineldeen DH, Hashimoto Y, Kohri K, Nakanishi M:Essential role of Chkl in S phase progression through regulation of RNR2 expression. Biochemical and Biophysical Research Communications 2008,374:79-83.
54. Ariumi Y, Kuroki M, Dansako H, Abe K, Ikeda M, Wakita T, Kato N:The DNA damage sensors ataxia-telangiectasia mutated kinase and checkpoint kinase 2 are required for hepatitis C virus RNA replication. J Virol 2008, 82:9639-9646.
55. Kitay-Cohen Y, Amiel A, Hilzenrat N, Buskila D, Ashur Y, Fejgin M, Gaber E, Safadi R, Tur-Kaspa R, Lishner M:Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type Ⅱ. Blood 2000,96:2910-2912.
56. Machida K, Cheng KTN, Sung VMH, Shimodaira S, Lindsay KL, Levine AM, Lai MY, Lai MMC:Hepatitis C virus induces a mutator phenotype: Enhanced mutations of immunoglobulin and protooncogenes. Proceedings of the National Academy of Sciences of the United States of America 2004, 101:4262-4267.
57. Machida K, Cheng KTH, Sung VMH, Lee KJ, Levine AM, Lai MMC: Hepatitis C virus infection activates the immunologic (type Ⅱ) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. Journal of Virology 2004,78:8835-8843.
58. Machida K, Cheng KTH, Lai CK, Jeng KS, Sung VMH, Lai MMC:Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. Journal of Virology 2006,80:7199-7207.
59. Baek KH, Park HY, Kang CM, Kim SJ, Jeong SJ, Hong EK, Park JW, Sung YC, Suzuki T, Kim CM, Lee CW:Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation. Journal of Molecular Biology 2006,359:22-34.
60. Lai CK, Jeng KS, Machida K, Cheng YS, Lai MMC:Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation. Virology 2008,370:295-309.
61. Machida K, McNamara G, Cheng KTH, Huang J, Wang CH, Comai L, Ou JHJ, Lai MMC:Hepatitis C Virus Inhibits DNA Damage Repair through Reactive Oxygen and Nitrogen Species and by Interfering with the ATM-NBS1/Mre11/Rad50 DNA Repair Pathway in Monocytes and Hepatocytes. Journal of Immunology 2010,185:6985-6998.
62. Hirano M, Kaneko S, Yamashita T, Luo H, Qin W, Shirota Y, Nomura T, Kobayashi K, Murakami S:Direct interaction between nucleolin and hepatitis C virus NS5B. JBiol Chem 2003,278:5109-5115.
63. Shimakami T, Honda M, Kusakawa T, Murata T, Shimotohno K, Kaneko S, Murakami S:Effect of hepatitis C virus (HCV) NS5B-nucleolin interaction on HCV replication with HCV subgenomic replicon. J Virol 2006, 80:3332-3340.
64. Goh PY, Tan YJ, Lim SP, Tan YH, Lim SG, Fuller-Pace F, Hong W:Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. J Virol 2004,78:5288-5298.
65. Kerkvliet J, Papke L, Rodriguez M:Antiviral effects of a transgenic RNA-dependent RNA polymerase. J Virol 2011,85:621-625.
66. von dem Bussche A, Machida R, Li K, Loevinsohn G, Khander A, Wang J, Wakita T, Wands JR, Li J:Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication. J Hepatol 2010,53:797-804.
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51. Jirmanova L, Bulavin DV, Fornace AJ, Jr.:Inhibition of the ATR/Chkl pathway induces a p38-dependent S-phase delay in mouse embryonic stem cells. Cell Cycle 2005, 4:1428-1434.
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56. Machida K, Cheng KTH, Sung VMH, Lee KJ, Levine AM, Lai MMC:Hepatitis C virus infection activates the immunologic (type Ⅱ) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. Journal of Virology 2004, 78:8835-8843.
57. Machida K, Cheng KTH, Lai CK, Jeng KS, Sung VMH, Lai MMC:Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. Journal of Virology 2006, 80:7199-7207.
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