Interaction of Quindoline derivative with telomeric repeat–containing RNA induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2

Zhang, Yan; Zeng, Deying; Cao, Jiaojiao; Wang, Mingxue; Shu, Bing; Kuang, Guotao; Ou, Tian‐Miao; Tan, Jia‐Heng; Gu, Lian‐Quan; Huang, Zhi‐Shu; Li, Ding

doi:10.1016/j.bbagen.2017.09.015

Cited by 26 publications

(23 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TRF2 may interact with G4 DNA through domains other than GAR, and the GAR domain is known to have functions in addition to TERRA binding. Another study found that another G4 interacting molecule CK1-14 bound TERRA and disrupted TRF2 binding to telomere repeat DNA 65 . In contrast, we found that NMM did not disrupt TRF2 binding to telomeric DNA, but did inhibit TRF2 binding to TERRA.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that TERRA can interact directly with the glycine-arginine rich (GAR) element (also referred to as RGG) in the TRF2 amino terminal basic domain 59 – 63 . Biophysical studies have found that the G4 structure formation of TERRA is required for TRF2 binding 64 , 65 . Our previous research indicated that TERRA interaction with TRF2 GAR was important for telomeric heterochromatin formation, ORC recruitment, and telomere DNA integrity 61 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

Mei

Deng

Vladimirova

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Telomere dysfunction causes chromosomal instability which is associated with many cancers and age-related diseases. The non-coding telomeric repeat-containing RNA (TERRA) forms a structural and regulatory component of the telomere that is implicated in telomere maintenance and chromosomal end protection. The basic N-terminal Gly/Arg-rich (GAR) domain of telomeric repeat-binding factor 2 (TRF2) can bind TERRA but the structural basis and significance of this interaction remains poorly understood. Here, we show that TRF2 GAR recognizes G-quadruplex features of TERRA. We show that small molecules that disrupt the TERRA-TRF2 GAR complex, such as N-methyl mesoporphyrin IX (NMM) or genetic deletion of TRF2 GAR domain, result in the loss of TERRA, and the induction of γH2AX-associated telomeric DNA damage associated with decreased telomere length, and increased telomere aberrations, including telomere fragility. Taken together, our data indicates that the G-quadruplex structure of TERRA is an important recognition element for TRF2 GAR domain and this interaction between TRF2 GAR and TERRA is essential to maintain telomere stability.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

Mei

Deng

Vladimirova

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Studies on Qingdainone have shown anti-tumor and anti-inflammatory effects [ 23 ]. Quindoline can cause cell cycle arrest, resulting in inhibition of cell proliferation and causing cell apoptosis [ 24 ]. Bisindigotin was found to dose-dependently inhibit TCDD-induced ethoxyresorufin O-demethylase (EROD) activity to achieve an anti-tumor effect [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Deciphering Key Pharmacological Pathways of Qingdai Acting on Chronic Myeloid Leukemia Using a Network Pharmacology-Based Strategy

Liu

et al. 2018

Med Sci Monit

View full text Add to dashboard Cite

Qingdai, a traditional Chinese medicine (TCM) used for the treatment of chronic myeloid leukemia (CML) with good efficacy, has been used in China for decades. However, due to the complexity of traditional Chinese medicinal compounds, the pharmacological mechanism of Qingdai needs further research. In this study, we investigated the pharmacological mechanisms of Qingdai in the treatment of CML using network pharmacology approaches.First, components in Qingdai that were selected by pharmacokinetic profiles and biological activity predicted putative targets based on a combination of 2D and 3D similarity measures with known ligands. Then, an interaction network of Qingdai putative targets and known therapeutic targets for the treatment of chronic myeloid leukemia was constructed. By calculating the 4 topological features (degree, betweenness, closeness, and coreness) of each node in the network, we identified the candidate Qingdai targets according to their network topological importance. The composite compounds of Qingdai and the corresponding candidate major targets were further validated by a molecular docking simulation.Seven components in Qingdai were selected and 32 candidate Qingdai targets were identified; these were more frequently involved in cytokine-cytokine receptor interaction, cell cycle, p53 signaling pathway, MAPK signaling pathway, and immune system-related pathways, which all play important roles in the progression of CML. Finally, the molecular docking simulation showed that 23 pairs of chemical components and candidate Qingdai targets had effective binding.This network-based pharmacology study suggests that Qingdai acts through the regulation of candidate targets to interfere with CML and thus regulates the occurrence and development of CML.

show abstract

“…The sub-cellular location of PXR or LINE-1 ORF-1p was examined by subcellular fractionation assays. 23 , 24 MHCC97-H cells, which were transfected with vectors or treated with agents, were then homogenized using a Dounce homogenizer, and the homogenate was centrifuged at 366× g for 10 minutes at 4°C to separate nuclear fraction. Next, the supernatant was centrifuged again at 13,201× g for 15 minutes at 4°C, and the final supernatant was the cytoplasmic fraction.…”

Section: Methodsmentioning

confidence: 99%

LINE-1 ORF-1p enhances the transcription factor activity of pregnenolone X receptor and promotes sorafenib resistance in hepatocellular carcinoma cells

Chang

Zeng

Liu

et al. 2018

CMAR

View full text Add to dashboard Cite

BackgroundLINE-1 ORF-1p is encoded by the human pro-oncogene LINE-1. Our previous work showed that LINE-1 ORF-1p could enhance the resistance of hepatocellular carcinoma (HCC) cells to antitumor agents. However, the mechanisms involved in LINE-1 ORF-1p-mediated drug resistance remain largely unknown.Materials and methodsThe endogenous mRNA level of LINE-1 ORF-1p in clinical HCC specimens was examined using quantitative PCR (qPCR). The prognosis of HCC patients was assessed using time to progression and overall survival. The transcription factor activity of pregnenolone X receptor (PXR) was examined using luciferase gene reporter assays, qPCR, chromatin immunoprecipitation assays and cellular subfraction assays. Protein interaction between LINE-1 ORF-1p and PXR was detected by co-immunoprecipitation. The effect of LINE-1 ORF-1p on sorafenib resistance in HCC cells was studied using in vitro and in vivo models.ResultsA high level of LINE-1 ORF-1p in clinical specimens was related to poor prognosis in patients who received sorafenib treatment. LINE-1 ORF-1p increased the transcription factor activity of PXR by interacting with PXR and enhancing its cytoplasmic/nuclear translocation, and recruiting PXR to its downstream gene promoter, in turn enhancing the expression of the sorafenib resistance-related genes, CYP3A4 and mdr-1. LINE-1 ORF-1p enhanced the resistance to and clearance of sorafenib in HCC cells.ConclusionLINE-1 ORF-1p enhances the transcription factor activation of PXR and promotes the clearance of and resistance to sorafenib in HCC cells.

show abstract

Interaction of Quindoline derivative with telomeric repeat–containing RNA induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2

Cited by 26 publications

References 40 publications

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

Deciphering Key Pharmacological Pathways of Qingdai Acting on Chronic Myeloid Leukemia Using a Network Pharmacology-Based Strategy

LINE-1 ORF-1p enhances the transcription factor activity of pregnenolone X receptor and promotes sorafenib resistance in hepatocellular carcinoma cells

Contact Info

Product

Resources

About