JOURNAL OF MOLECULAR MODELING
·
2015
·Vol. 21
·期 11
·1-7
·
IF 1.736
Zhao Dongxin,Lu Kui
Breast cancer susceptibility gene 2 (BRCA2)—a human tumor suppressor gene—is related to various malignancies such as breast and ovarian cancer. This gene can induce the key protein RAD51 recombinase, which is involved in homologous recombination with single-stranded DNA in the human body and can regulate RAD51 to complete the repair of damaged double-stranded DNA. Eight highly conserved BRC repeat motifs in BRCA2 protein serve as sites for the interaction between BRCA2 and RAD51. BRCA2 regulates RAD51 through these motifs. However, the mechanism of this interaction still requires further research. In this study, the BRC4 motif that demonstrated strong interaction with RAD51 was selected as template peptide. On the basis of known data regarding the crystal structure of the BRC4-RAD51(191–220) complex, a series of BRC4 mutants was designed using PyMOL software based on the sequence of BRC4, and polypeptides were synthesized by the Fmoc solid-phase method. After purification by reversed-phase high-performance liquid chromatography, the purity of the polypeptides reached >95 %. The primary determination of circular dichroism spectra showed that the polypeptides exhibited slight changes in secondary structure, which indicated that mutation on the non-conserved sites in BRC4 probably affected the interaction with BRC4. These findings will facilitate research on the interaction between targeting peptides and BRC4 mutants, as well the basic rules covering this interaction.
研究领域:
分子生物学
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结构生物学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Translational Oncology
·
2025
·
IF 4.1
Zhe Qin,Fangzhou Ye,Jiayi Wang,Jun Jiang,Xiaohong Zhang,Huanqing Li,Li Feng
Background Cisplatin resistance significantly impedes the treatment of gastric cancer (GC). This work examined the possible therapeutic target status and function of BUB1B in controlling cisplatin resistance. Methods Following the identification of differentially expressed genes (DEGs), protein-protein interaction (PPI) network analysis was conducted using datasets from the Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD), GSE51575, and GSE79973. Functional tests assessed the effect of BUB1B overexpression and knockdown on the GC cells. Enrichment analysis and RNA-seq identified pathways linked to BUB1B . Additionally, the function of BUB1B in GC cells resistant to cisplatin in regulating DNA repair was examined, as its relationship with Rad51 inhibitor (B02) in regulating cell cycle, proliferation, and apoptosis. The combined effects of Rad51 suppression and BUB1B overexpression on tumor development in cisplatin-resistant GC cells were further validated in vivo xenograft models. Results Significant overexpression of six critical overlapping genes was seen in GC tissues. The GC cell invasion, migration, and proliferation processes were improved by BUB1B overexpression, whereas BUB1B knockdown prevented these outcomes. Genes involved in DNA repair were downregulated by BUB1B knockdown, according to an RNA-seq study. BUB1B overexpression boosted cell survival via modulating cell cycle proteins, but BUB1B knockdown hampered DNA repair and increased death in cisplatin-resistant GC cells. Overexpression of BUB1B enhanced tumor development in vivo and counteracted the inhibitory effects of B02 on cell growth. Conclusion BUB1B enhances cisplatin resistance in gastric cancer by regulating DNA repair and cell cycle progression, suggesting that targeting BUB1B may be a feasible therapeutic strategy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2016
·Vol. 45
·期 6
·e45
·
IF 9.202
Zhai Junqiu,Liu Yibin,Huang Shan,Fang Simin,Zhao Meiping
Human apurinic/apyrimidinic endonuclease/redox effector factor 1 (APE1) is an essential DNA repair protein. Herein, we demonstrate that avidin-oriented abasic site-containing DNA strands (AP-DNA) on the surface of silica coated magnetic nanoparticles (SiMNP) can selectively respond to APE1 while resist the digestion by other nucleases. Mechanism studies have revealed that avidin may serve as an organizer protein and recruit APE1 to the DNA substrates on the nanoparticles via strong and specific interactions. Taking advantage of this newly disclosed property, we for the first time successfully displayed the intracellular activities of APE1 in living cells by fluorescence imaging. The avidin organized AP-DNA-SiMNP assembly holds great potential for enzyme-mediated release of drugs inside tumor cells which often contain higher levels of APE1 than normal cells.
研究领域:
分子生物学
·
医学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 24
·20366-20373
·
IF 3.289
Yuwei Cong,Zigui Wang,Shasha He,Dongfang Zhou,Jizhen Li,Zhigang Xie,Xuesi Chen,Xiabin Jing,Yubin Huang
Platinum(II) complexes are used for treating over half of cancers in the clinic. However, their application is accompanied with acquired resistance and severe toxic side effects. To address these challenges, a multifunctional single drug constructed from a photo-activated oxaliplatin(IV) complex and DMC was conjugated to polymer to form multifunctional single-drug-loaded nanoparticles. When the nanoparticles are internalized by cancer cells via endocytosis, active oxaliplatin(II) can be released upon UVA irradiation to attack DNA, while DMC will be hydrolyzed subsequently from the polymer chain within the intracellular environment to block DNA repair by PP2A inhibition. The multifunctional single-drug-loaded nanoparticles exhibited enhanced anti-cancer efficacy and decreased toxicity compared to oxaliplatin(II) in vitro and in vivo. This enhanced cancer treatment strategy could have potential clinical use in the near future.
研究领域:
肿瘤学
·
药剂学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2020
·
IF 7.1
Yuqiang Hu,Zhen Zhang,Weicong Ye,Wei Zhang,Minghao Hu,Wenqian Yuan,Hongbo Wang,Xianjin Xiao,Tongbo Wu
Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a crucial role in DNA repair and gene regulation. The abnormal variations of the concentration of APE1 in the human blood and tissue cells are highly correlated to various diseases. Thus, APE1 can be used as a biomarker to aid clinical diagnosis of diseases. Detection of APE1 activity with high sensitivity and selectivity simultaneously is difficult to achieve. Here we provide a DNA structure-mediated fluorescent biosensor to solve the above problem. Upon the existence of APE1, the apurinic/apyrimidinic site will be cleaved, and the terminal structure of the hairpin DNA substrate will change. Then the terminal deoxynucleotidyl transferase and endonuclease IV could provide dual fluorescent signal amplification. Through the ingenious structure design of the biosensor, we have improved the reactivity of APE1 and minimized the interference of other enzymes. The results indicate that the detection limit for APE1 is as low as 1.7 × 10 −6 U/mL. The biosensor has been successfully applied to the detection of APE1 in real biological samples and the screening of APE1 inhibitors.
研究领域:
生物化学
·
分子生物学
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医学诊断
✓ 已验证
产品关联
DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Lanlan Chen,Jingjing Lai,Siqi Dong,Wenjun Liu,Ximei Zhang,Huanghao Yang
Evaluating tumor radiosensitivity is beneficial for the prediction of treatment efficacy, customization of treatment plans, and minimization of side effects. Tracking the mitochondrial DNA (mtDNA) repair process helps to assess tumor radiosensitivity as mtDNA repair determines the fate of the cell under radiation-induced mtDNA damage. However, current probes developed to monitor levels of DNA repair enzymes suffered from complex synthesis, uncontrollable preparation, limited tumor selectivity, and poor organelle-targeting ability. Especially, the correlation between mtDNA repair activity and inherent radiosensitivity of tumors has not yet been explored. Here, we present a mitochondria-targeted DNA-based nanoprobe (TPP-Apt-tFNA) for in situ monitoring of the activity of the mtDNA repair enzyme and evaluating tumor radiosensitivity. TPP-Apt-tFNA consists of a DNA tetrahedral framework precisely modified with three functional modules on each of the three vertexes, that is, the tumor cell-targeting aptamer, the mitochondrion-targeting moiety, and the apurinic/apyrimidinic endonuclease 1 (APE1)-responsive molecule beacon. Once selectively internalized by tumor cells, the nanoprobe targeted the mitochondrion and specifically recognized APE1 to activate fluorescence, allowing the observation of mtDNA repair activity. The nanoprobe showed elevated APE1 levels in the mitochondria of tumor cells under oxidative stress. Moreover, the nanoprobe enabled the illumination of different levels of APE1-mediated mtDNA repair activity in different cell cycle phases. Furthermore, using the nanoprobe in vitro and in vivo, we found that tumor cells with high activity of mtDNA repair, which allowed them to recover from radiation-induced mtDNA lesions, had low sensitivity to radiation and an unsatisfactory radiotherapy outcome. Our work provides a new imaging tool for exploring the roles of mtDNA repair activity in diverse biological processes and for guiding tumor radiation treatment.
研究领域:
生物化学
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分子生物学
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医学影像学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2019
·
IF 3.743
Tianhua Liu,Ling Zuo,Dongqing Guo,Xinlou Chai,Jie Xu,Zhaorui Cui,Zhiyi Wang,Chunying Hou
Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Junzhuo Shan,Yixiao Sheng,Lun Luo,Wenhai Wang,Xinjiang Liu,Yi Ma,Jufang Wang
Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme involved in DNA repair and cellular redox regulation, and is frequently overexpressed in tumor cells. This highlights the urgent need for a rapid and high-sensitive point-of-care testing (POCT) strategy for APE1 to facilitate early cancer diagnosis. Rolling circle amplification (RCA) is a widely used isothermal DNA amplification method; however, its application in APE1 detection remains rare. Here, we introduce a versatile RCA-Lock (Rlock) conversion platform that enables the transformation of RCA-based nucleic acid detection technologies into APE1-responsive assays. Building upon this platform, we further developed a novel POCT method for APE1 detection─Rlock-mediated, CRISPR/Cas12a-driven RCA cycle (RCRE)─which, for the first time, integrates CRISPR/Cas12a with RCA into a one-pot APE1 detection system. The RCRE assay achieves a limit of detection of 8.86 × 10–4 U/mL within 30 min, while requiring minimal equipment, low cost, and no complex handling procedures. This Rlock-based conversion strategy represents a transformative advance in the field of APE1 diagnostics and offers conceptual inspiration for the design of programmable nucleic acid–based biosensors. The resulting RCRE assay significantly broadens the technological landscape for early cancer detection and paves the way for future clinical translation.
研究领域:
分子诊断学
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生物化学
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生物技术
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癌症研究
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遗传学
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分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Sensors
·
2021
·
IF 7.711
Chao Jiang,Fangfang Wang,Kexin Zhang,Tiantian Min,Desheng Chen,Yongqiang Wen
In the deoxyribonucleic acid (DNA) repair pathways, DNA repair enzymes have great significance for genomic integrity. As one important initiator of the base-excision repair pathway, the aberrant activity of uracil-DNA glycosylase (UDG) is closely associated with many diseases. Herein, we developed a simple distance-based device for visual detection of UDG activity using a load-free DNA hydrogel. The DNA hydrogel consists of polyacrylamide–DNA chains being bridged by a single-stranded DNA crosslinker containing a responsive uracil base site. UDG can recognize and remove the uracil, resulting in the cleavage effect of the DNA crosslinker strand with the assistance of endonuclease IV (Endo IV). Plugging one end of the capillary tube, the DNA hydrogel acting as a filter membrane separator would control molecules to flow into the tube. The integrity of the DNA hydrogel networks is affected by the excision of UDG. Therefore, taking full advantage of membrane filtration of the DNA hydrogel, the activity of UDG can be quantitatively detected via reading the distance of the red indicator solution in the capillary tube. Without any instruments and complicated procedures, this method realizes high sensitivity and specificity for the detection of UDG as low as 0.02 mU/mL and can even measure UDG in complex cell samples. Additionally, this method is simple, universal, and can be used to screen inhibitors, which shows great potential for point-of-care testing, clinical diagnosis, and drug discovery.
研究领域:
生物化学
·
分子生物学
·
医学诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Yutong Shao,Miaomiao Chen,Wenlong Chen,Zehui Wang,Mengzhang Sui,Mingyu Tian,Yingnan Wu,Jitao Song,Debin Ji,Fengling Song
Photodynamic therapy (PDT) uses photosensitizers to convert oxygen (O 2 ) to reactive oxygen species (ROS) under irradiation to induce DNA damage and kill cancer cells. However, the effect of PDT is usually alleviated by apoptosis resistance mechanism of tumor living cells. MTH1 enzyme is known to be such an apoptosis-resistance enzyme which is over expressed as a scavenger to repair the damaged DNA. In this work, a hypoxia-activated nanosystem FTPA, which can be degraded to release the encapsulated PDT photosensitizer 4-DCF-MPYM and an inhibitor TH588 is proposed. The inhibitor TH588 can inhibit the DNA repair process by reducing the activity of MTH1 enzyme, and achieve the purpose of amplifying the therapeutic effect of PDT. This work demonstrates that a precise and augmented tumor PDT is achieved by integration of hypoxia-activation and inhibition resistance of tumor cells to apoptosis.
研究领域:
癌症治疗
·
纳米技术
·
生物化学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
VIROLOGY
·
2023
·
IF 3.7
Xiaoping Huang,Xiao Wang,Yaqi Sun,Ling Li,Anna Li,Wentao Xu,Xiaolan Xie,Yong Diao
Because it is safe and has a simple genome, recombinant adeno-associated virus (rAAV) is an extremely appealing vector for delivery in in vivo gene therapy. However, its low transduction efficiency for some cells, limits its further application in the field of gene therapy. Bleomycin is a chemotherapeutic agent approved by the FDA whose effect on rAAV transduction has not been studied. In this study, we systematically investigated the effect of Bleomycin on the second-strand synthesis and used CRISPR/CAS9 and RNAi methods to understand the effects of Bleomycin on rAAV vector transduction, particularly the effect of DNA repair enzymes. The results showed that Bleomycin could promote rAAV2 transduction both in vivo and in vitro. Increased transduction was discovered to be a direct result of decreased cytoplasmic rAAV particle degradation and increased second-strand synthesis. TDP1 , PNKP , and SETMAR are required to repair the DNA damage gap caused by Bleomycin, TDP1, PNKP, and SETMAR promote rAAV second-strand synthesis. Bleomycin induced DNA-PKcs phosphorylation and phosphorylated DNA-PKcs and Artemis promoted second-strand synthesis. The current study identifies an effective method for increasing the capability and scope of in-vivo and in-vitro rAAV applications, which can amplify cell transduction at Bleomycin concentrations. It also supplies information on combining tumor gene therapy with chemotherapy.
研究领域:
分子生物学
·
基因治疗
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癌症研究
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Reziyamu Wufuer,Keli Liu,Jing Feng,Meng Wang,Shaofan Hu,Feilong Chen,Shanshan Lin,Yiguo Zhang
Cisplatin ( cis -Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors . The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion ( Cl − ) in its structure with H 2 O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks . To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair , but the hyperactive Nrf2 in Nrf1α –∕– cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）