羧基化单壁碳纳米管对端粒酶及端粒的生物医学效应
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摘要
端粒位于染色体的末端，在保护染色体的完整性，使其免受异常的重组，降解以及末端融合中发挥重要的作用。端粒由含有很多重复单元的富G和富C的双链DNA组成，此外还有一个富G的单链3′-末端。其富G序列可以形成分子内或分子间的G-quadruplex四链结构，其互补的富C序列可以形成i-motif四链结构。已知端粒的富G序列和富C序列都可以作为癌症治疗的靶点，G-quadruplex结构的形成和稳定已经证实能够显著抑制端粒酶的活性，而且目前也有很多通过稳定G-quadruplex结构以抑制端粒酶活性的配体。但是，由于i-motif结构的不稳定性，以及缺乏其特异性的结合配体，i-motif结构的生物学活性还没有得到充分地阐明，特别是其结构的形成和稳定能否抑制端粒酶的活性还未知。
近年来，碳纳米管由于其独特的性质，其作为一种特异性的配体与DNA的相互作用已经得到越来越多的关注。我们课题组就此也开展了很多工作，我们发现SWNTs可以去稳定双链DNA,而且诱导序列特异性的B-A转换，而且SWNTs也可以诱导单链的RNApoly(rA)自组装成A·A~+双链结构。特别的是，我们观察到单壁碳纳米管而不是多壁碳纳米管，可以选择性的稳定人端粒i-motif结构。这使SWNTs成为第一个可以选择性结合i-motif的配体，并可以用来分析i-motif结构的形成在体内外的生物学活性。
在本论文中，我们应用TRAP-G4assay，传统的TRAP assay，免疫荧光，免疫印迹，免疫沉淀，染色质免疫沉淀以及端粒荧光原位杂交分析SWNTs作用后对端粒酶的活性，端粒结构及细胞增殖的影响。本论文的主要观点如下：
1.通过对SWNTs进行PEG修饰，之后再进行FITC标记，我们观察到SWNTs可以进入细胞核，而且可以定位在端粒，因为它与端粒定位的标志物TRF1蛋白实现了共定位，这为SWNTs在细胞内的生物学活性特别是在端粒的可能活性提供了依据；
2.通过TRAP-G4assay,我们发现SWNTs可以在细胞外抑制端粒酶的活性，这可能是由于SWNTs诱导端粒富C链形成i-motif结构，而使其互补的富G链形成G-quadruplex结构,进而抑制端粒酶的活性。SWNTs对端粒酶活性的抑制作用也在细胞内得到证实。而且，进一步分析发现这种端粒酶的抑制作用并不依赖于其定位的变化或者表达的变化；
3.虽然SWNTs不诱导急性细胞毒性，但是在较高浓度下，经过稍长时间的作用还是可以诱导细胞的生长抑制的，这种生长抑制可能与端粒结构的紊乱相关，而不仅仅是依赖端粒酶活性的抑制。而且进一步研究发现SWNTs诱导的生长抑制通常与DNA损伤反应的产生密切相关。而且，进一步证实这种DNA损伤反应是发生在端粒上的；
4. SWNTs可以诱导端粒结构的紊乱，引起后期桥，微核的形成及端粒的融合等染色体的异常。而且，通过端粒-末端脱氧核糖核酸转移酶（TdT）的共定位分析可以直接观察到SWNTs作用之后端粒的去保护状态；
5.通过免疫荧光和染色质免疫沉淀分析，SWNTs可以促进端粒相关蛋白（TRF2,POT1和PCBP1）从端粒上解离，这也为细胞内G-quadruplex及i-motif结构的形成提供间接的证据。而且，进一步研究发现，SWNTs可以促进端粒3′-悬端的快速的降解，但是却不影响整体端粒的长度；
6. SWNTs可以诱导细胞周期的阻滞，凋亡以及衰老，这可能是由于端粒结构的紊乱所造成的，而且这些生物学效应也p16和p21蛋白的上调密切相关。本研究第一次证明了，稳定端粒i-motif结构可以抑制端粒酶的活性，并影响端粒的功能，这为理解SWNTs在癌细胞中的生物医学效应，以及i-motif结构在细胞内的生物学活性都具有重要的意义。
Telomeres play important roles in chromosome structural integrity to cap and protecttheir extremities from illegitimate recombination, degradation and end-to-end fusion.In humans, the telomere is composed of G-rich and C-rich duplex with asingle-stranded3′-overhang, the G-rich strand can form a four-stranded G-quadruplexstructure, and its complementary C-rich strand may adopt intercalated i-motifstructures. Both human telomeric G-rich and C-rich DNA have been considered asspecific drug targets for cancer therapy. G-quadruplex formation can inhibittelomerase activity. Many compounds that can stabilize G-quadruplex structure andinhibit telomerase activity have been reported. However, due to i-motif structureunstable and lack of i-motif specific binding agents, it remains unclear whetherstabilization of i-motif structure can inhibit telomerase activity.
Single-walled carbon nanotubes (SWNTs) have been considered as the leadingnanodevice candidate, whose interactions with nucleic acids has attracted muchattention. A series of DNA interactions with SWNTs have been studied by our group.We found that SWNTs can destabilize duplex DNA and induce a sequence-dependentDNA B-A transition, and can facilitate self-structuring of single-stranded RNApoly(rA) to form A·A~+duplex structure. Intriguingly, SWNTs, not multi-walledcarbon nanotubes (MWNTs), can selectively stabilize human telomeric i-motif DNAand induce i-motif structure formation by binding to the5′-end major groove underphysiological conditions, and even under molecular crowding conditions. Furtherstudies indicate that SWNTs do not stabilize G-quadruplex DNA, and can causehuman telomeric duplex to disassociate by forming i-motif and G-quadruplexDNA. This makes SWNTs as the first selective i-motif DNA binding agent andsuitable probe to study the biological function of i-motif both in vitro and in livingcells.
In this report, we applied TRAP-G4assay, conventional TRAP assay,immunofluorescence, immunoblot, immunoprecipitation, ChIP and telomere-FISH toanalyze the effects of SWNTs on telomerase activity, telomere structure and cellproliferation. The main results are as follows:
1. SWNTs can enter the nucleus and localize at telomere when modified with PEG and labeled with FITC, which is clarified by the co-localization with interphasetelomere marker TRF1protein. This result may provide the possible biologicalactivities of SWNTs in living cells, especially at telomere.
2. Based on TRAP-G4assay, SWNTs can inhibit telomerase activity in vitro throughthe indirect G-quadruplex stabilization on the telomeric G-rich strand induced by theformation of i-motif on the complementary C-rich strand. This has been confirmed inliving systems. Furthermore, the decreased telomerase activity in living cells was notassociated with the alteration of its localization or expression.
3. Although SWNTs did not induce acute cytotoxicity, after a long time exposure,SWNTs can inhibit cell growth, which may be related to the telomere dysfunction, butnot merely to the telomerase activity inhibition. Furthermore, growth arrest inducedby SWNTs was associated with the production of DNA damage response, which wasfurther clarified to occur at telomere.
4. SWNTs can induce telomere dysfunction characterized by the formation ofanaphase bridges, micronuclei and telomere fusion. SWNTs also induced the directunprotection of telomere visualized by the telomere-TdT assay.
5. SWNTs can induce the reveal of telomere binding protein TRF2, POT1and PCBP1from telomere, which may provide the indirect evidence for G-quadruplex and i-motifformation in living cells. Moreover, SWNTs treatment caused the rapid degradationof telomeric3′-overhang from telomere without affecting the total telomere length.
6. SWNTs induced the cell cycle arrest, apoptosis and senescence as consequence oftelomere dysfunction. This growth suppression maybe associated with theupregulation of p16and p21proteins.
This is the first example that stabilization of i-motif structure can inhibit telomeraseactivity and interfere with the telomere functions in cancer cells. Our work mayprovide new insights into understanding the biomedical effects of SWNTs in cancercells and the biological importance of i-motif structure in vivo.
近年来，碳纳米管由于其独特的性质，其作为一种特异性的配体与DNA的相互作用已经得到越来越多的关注。我们课题组就此也开展了很多工作，我们发现SWNTs可以去稳定双链DNA,而且诱导序列特异性的B-A转换，而且SWNTs也可以诱导单链的RNApoly(rA)自组装成A·A~+双链结构。特别的是，我们观察到单壁碳纳米管而不是多壁碳纳米管，可以选择性的稳定人端粒i-motif结构。这使SWNTs成为第一个可以选择性结合i-motif的配体，并可以用来分析i-motif结构的形成在体内外的生物学活性。
在本论文中，我们应用TRAP-G4assay，传统的TRAP assay，免疫荧光，免疫印迹，免疫沉淀，染色质免疫沉淀以及端粒荧光原位杂交分析SWNTs作用后对端粒酶的活性，端粒结构及细胞增殖的影响。本论文的主要观点如下：
1.通过对SWNTs进行PEG修饰，之后再进行FITC标记，我们观察到SWNTs可以进入细胞核，而且可以定位在端粒，因为它与端粒定位的标志物TRF1蛋白实现了共定位，这为SWNTs在细胞内的生物学活性特别是在端粒的可能活性提供了依据；
2.通过TRAP-G4assay,我们发现SWNTs可以在细胞外抑制端粒酶的活性，这可能是由于SWNTs诱导端粒富C链形成i-motif结构，而使其互补的富G链形成G-quadruplex结构,进而抑制端粒酶的活性。SWNTs对端粒酶活性的抑制作用也在细胞内得到证实。而且，进一步分析发现这种端粒酶的抑制作用并不依赖于其定位的变化或者表达的变化；
3.虽然SWNTs不诱导急性细胞毒性，但是在较高浓度下，经过稍长时间的作用还是可以诱导细胞的生长抑制的，这种生长抑制可能与端粒结构的紊乱相关，而不仅仅是依赖端粒酶活性的抑制。而且进一步研究发现SWNTs诱导的生长抑制通常与DNA损伤反应的产生密切相关。而且，进一步证实这种DNA损伤反应是发生在端粒上的；
4. SWNTs可以诱导端粒结构的紊乱，引起后期桥，微核的形成及端粒的融合等染色体的异常。而且，通过端粒-末端脱氧核糖核酸转移酶（TdT）的共定位分析可以直接观察到SWNTs作用之后端粒的去保护状态；
5.通过免疫荧光和染色质免疫沉淀分析，SWNTs可以促进端粒相关蛋白（TRF2,POT1和PCBP1）从端粒上解离，这也为细胞内G-quadruplex及i-motif结构的形成提供间接的证据。而且，进一步研究发现，SWNTs可以促进端粒3′-悬端的快速的降解，但是却不影响整体端粒的长度；
6. SWNTs可以诱导细胞周期的阻滞，凋亡以及衰老，这可能是由于端粒结构的紊乱所造成的，而且这些生物学效应也p16和p21蛋白的上调密切相关。本研究第一次证明了，稳定端粒i-motif结构可以抑制端粒酶的活性，并影响端粒的功能，这为理解SWNTs在癌细胞中的生物医学效应，以及i-motif结构在细胞内的生物学活性都具有重要的意义。
Telomeres play important roles in chromosome structural integrity to cap and protecttheir extremities from illegitimate recombination, degradation and end-to-end fusion.In humans, the telomere is composed of G-rich and C-rich duplex with asingle-stranded3′-overhang, the G-rich strand can form a four-stranded G-quadruplexstructure, and its complementary C-rich strand may adopt intercalated i-motifstructures. Both human telomeric G-rich and C-rich DNA have been considered asspecific drug targets for cancer therapy. G-quadruplex formation can inhibittelomerase activity. Many compounds that can stabilize G-quadruplex structure andinhibit telomerase activity have been reported. However, due to i-motif structureunstable and lack of i-motif specific binding agents, it remains unclear whetherstabilization of i-motif structure can inhibit telomerase activity.
Single-walled carbon nanotubes (SWNTs) have been considered as the leadingnanodevice candidate, whose interactions with nucleic acids has attracted muchattention. A series of DNA interactions with SWNTs have been studied by our group.We found that SWNTs can destabilize duplex DNA and induce a sequence-dependentDNA B-A transition, and can facilitate self-structuring of single-stranded RNApoly(rA) to form A·A~+duplex structure. Intriguingly, SWNTs, not multi-walledcarbon nanotubes (MWNTs), can selectively stabilize human telomeric i-motif DNAand induce i-motif structure formation by binding to the5′-end major groove underphysiological conditions, and even under molecular crowding conditions. Furtherstudies indicate that SWNTs do not stabilize G-quadruplex DNA, and can causehuman telomeric duplex to disassociate by forming i-motif and G-quadruplexDNA. This makes SWNTs as the first selective i-motif DNA binding agent andsuitable probe to study the biological function of i-motif both in vitro and in livingcells.
In this report, we applied TRAP-G4assay, conventional TRAP assay,immunofluorescence, immunoblot, immunoprecipitation, ChIP and telomere-FISH toanalyze the effects of SWNTs on telomerase activity, telomere structure and cellproliferation. The main results are as follows:
1. SWNTs can enter the nucleus and localize at telomere when modified with PEG and labeled with FITC, which is clarified by the co-localization with interphasetelomere marker TRF1protein. This result may provide the possible biologicalactivities of SWNTs in living cells, especially at telomere.
2. Based on TRAP-G4assay, SWNTs can inhibit telomerase activity in vitro throughthe indirect G-quadruplex stabilization on the telomeric G-rich strand induced by theformation of i-motif on the complementary C-rich strand. This has been confirmed inliving systems. Furthermore, the decreased telomerase activity in living cells was notassociated with the alteration of its localization or expression.
3. Although SWNTs did not induce acute cytotoxicity, after a long time exposure,SWNTs can inhibit cell growth, which may be related to the telomere dysfunction, butnot merely to the telomerase activity inhibition. Furthermore, growth arrest inducedby SWNTs was associated with the production of DNA damage response, which wasfurther clarified to occur at telomere.
4. SWNTs can induce telomere dysfunction characterized by the formation ofanaphase bridges, micronuclei and telomere fusion. SWNTs also induced the directunprotection of telomere visualized by the telomere-TdT assay.
5. SWNTs can induce the reveal of telomere binding protein TRF2, POT1and PCBP1from telomere, which may provide the indirect evidence for G-quadruplex and i-motifformation in living cells. Moreover, SWNTs treatment caused the rapid degradationof telomeric3′-overhang from telomere without affecting the total telomere length.
6. SWNTs induced the cell cycle arrest, apoptosis and senescence as consequence oftelomere dysfunction. This growth suppression maybe associated with theupregulation of p16and p21proteins.
This is the first example that stabilization of i-motif structure can inhibit telomeraseactivity and interfere with the telomere functions in cancer cells. Our work mayprovide new insights into understanding the biomedical effects of SWNTs in cancercells and the biological importance of i-motif structure in vivo.
引文
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