G-quadruplex(G4)is one of the higher-order DNA structures in guanine-rich sequences which are widely distributed across the genome.Due to their presence in oncogenic promoters and telomeres,G4 DNA structures become th...G-quadruplex(G4)is one of the higher-order DNA structures in guanine-rich sequences which are widely distributed across the genome.Due to their presence in oncogenic promoters and telomeres,G4 DNA structures become the novel targets in anticancer drug designs.Curaxin CBL0137,as an important candidate anticancer drug,can effectively inhibit the growth of multiple cancers.Although there is evidence that anticancer activity of curaxin is associated with its ability to bind DNA and to change the DNA topology,its therapeutic target and the underlying anti-cancer mechanism are still unclear.Here we show,for the first time,that curaxin CBL0137 induces G4 folding from anti-parallel to parallel structures,by single-molecule fluorescence resonance energy transfer technique.More importantly,we find that curaxin CBL0137 promotes G4 folding as well as stabilizes the folded G4 structures with long loops,giving a novel insight into effects of curaxin CBL0137 on DNA structures.Our work provides new ideas for the therapeutic mechanism of curaxin CBL0137 and for designs of new G4-targeting anticancer drugs.展开更多
Intracellular diffusion is critical for molecule translocation in cytoplasm and mediates many important cellular processes.Meanwhile,the diffusion dynamics is affected by the heterogeneous cytoplasm.Previous studies o...Intracellular diffusion is critical for molecule translocation in cytoplasm and mediates many important cellular processes.Meanwhile,the diffusion dynamics is affected by the heterogeneous cytoplasm.Previous studies on intracellular diffusion are mainly based on two-dimensional(2 D)measurements under the assumption that the three-dimensional(3 D)diffusion is isotropic.However,the real behaviors of 3 D diffusion of molecules in cytoplasm are still unclear.Here,we have built a 3 D single-particle tracking(SPT)microscopy and studied the 3 D diffusion of quantum dots(QDs)in adherent A549 cells.Notably,we found that the intracellular diffusion of QDs is quasi-2 D,with the axial motion being severely confined.Further investigations demonstrated that disrupting the cytoskeleton component or endoplasmic reticulum(ER)does not alter the quasi-2 D diffusion pattern,although ER reduces the diffusion rates and slightly relieves the constraint in the axial diffusion.The preferred quasi-2 D diffusion is quite robust and attributed to the complex cytoarchitectures in the flat adherent cells.With the aid of 3 D SPT method,the quasi-2 D diffusion in cells was revealed,shedding new light on the physical nature of cytoplasm.展开更多
基金Supported by the National Natural Science Foundation ofChina ( No . 60025516 , No . 10334100 , and No .60138010 )the Innovation Project of the ChineseAcademy of Sciences ,K.C.Wong Post-doctoral ResearchAward ( No .40 )partly supported by NationalCenter for Nanoscience and Technology
基金ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China （No.11274374）, the National Basic Research Program of China （No.2009CB930704）, and the Basic Scientific Research Foundation of China Agricultural University （No.2012QJ026）.
基金supported by the National Natural Science Foundation of China(Grant Nos.10225417,21991133,12122402,and 12074043)the National Basic Research Program of China(Grant No.2006CB601003)。
文摘G-quadruplex(G4)is one of the higher-order DNA structures in guanine-rich sequences which are widely distributed across the genome.Due to their presence in oncogenic promoters and telomeres,G4 DNA structures become the novel targets in anticancer drug designs.Curaxin CBL0137,as an important candidate anticancer drug,can effectively inhibit the growth of multiple cancers.Although there is evidence that anticancer activity of curaxin is associated with its ability to bind DNA and to change the DNA topology,its therapeutic target and the underlying anti-cancer mechanism are still unclear.Here we show,for the first time,that curaxin CBL0137 induces G4 folding from anti-parallel to parallel structures,by single-molecule fluorescence resonance energy transfer technique.More importantly,we find that curaxin CBL0137 promotes G4 folding as well as stabilizes the folded G4 structures with long loops,giving a novel insight into effects of curaxin CBL0137 on DNA structures.Our work provides new ideas for the therapeutic mechanism of curaxin CBL0137 and for designs of new G4-targeting anticancer drugs.
基金supported by the National Natural Science Foundation of China(Grant Nos.11674383,11874415,21991133,11774407)the National Key Research and Development Program(Grant No.2016YFA0301500)+1 种基金the Youth Innovation Promotion Association of CAS(Grant No.2019006)the Fundamental Research Funds for the Central Universities(Grant No.2019NTST26)。
文摘Intracellular diffusion is critical for molecule translocation in cytoplasm and mediates many important cellular processes.Meanwhile,the diffusion dynamics is affected by the heterogeneous cytoplasm.Previous studies on intracellular diffusion are mainly based on two-dimensional(2 D)measurements under the assumption that the three-dimensional(3 D)diffusion is isotropic.However,the real behaviors of 3 D diffusion of molecules in cytoplasm are still unclear.Here,we have built a 3 D single-particle tracking(SPT)microscopy and studied the 3 D diffusion of quantum dots(QDs)in adherent A549 cells.Notably,we found that the intracellular diffusion of QDs is quasi-2 D,with the axial motion being severely confined.Further investigations demonstrated that disrupting the cytoskeleton component or endoplasmic reticulum(ER)does not alter the quasi-2 D diffusion pattern,although ER reduces the diffusion rates and slightly relieves the constraint in the axial diffusion.The preferred quasi-2 D diffusion is quite robust and attributed to the complex cytoarchitectures in the flat adherent cells.With the aid of 3 D SPT method,the quasi-2 D diffusion in cells was revealed,shedding new light on the physical nature of cytoplasm.
