Novel Interaction of the Z-DNA Binding Domain of Human ADAR1 with the Oncogenic c-Myc Promoter G-Quadruplex

Kang, Hong Je; Le, Tuong Vy Thi; Kim, Kyungmin; Hur, Jeonghwan; Kim, Kyeong Kyu; Park, Hyun-Ju

doi:10.1016/j.jmb.2014.05.001

Cited by 30 publications

(22 citation statements)

References 57 publications

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“…A total of 61 ligands were tested at 100 lM and then 18 ligands [43] demonstrated that C6 (C) had a low selectivity over the mutant, while B5 (S), C2 (C) and D2 (C) showed more than 4.5-fold selectivity for the WT, and these three ligands were chosen for further evaluation (Fig. 3a).…”

Section: Biochemical Evaluationmentioning

confidence: 99%

“…Representative G-quadruplex binding ligands, 307A (blue carbon), Braco-19 (orange carbon) and TMPyP4 (yellow carbon), were aligned and common pharmacophores (Acceptor site, Donor atom and Hydrophobic center) were determined for UNITY-3D search. b A docked structure of c-MYC promoter G-quadruplex (cyan) and TMPyP4 as a reference with low binding energy G-quadruplex structure disrupting the third G-tract and then increase the expression of luciferase [37,43]. Transfected cells were treated with ligands for 48 h. As a result, B5, C2 and D2 selectively inhibit luciferase activity of wild-type (Fig.…”

Section: Biochemical Evaluationmentioning

confidence: 99%

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In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kang

Park

2014

J Comput Aided Mol Des

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G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity.

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Section: Biochemical Evaluationmentioning

confidence: 99%

Section: Biochemical Evaluationmentioning

confidence: 99%

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kang

Park

2014

J Comput Aided Mol Des

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“…Although its binding to Z-DNA is well documented, a structurally related protein, ZBP-1/DLM-1, which has been clearly shown to bind Z-DNA [30], is instead a physiologically broad-range DNA sensor involved in innate immunity. Moreover, the recent report of Kang et al [31], which stated that ADAR-1 is a G-quadruplex binding protein, called the Z-DNA binding specificity of ADAR into question. Therefore, a bona fide Z-DNA-detecting reagent, which binds Z-DNA specifically, regardless of sequence, and exhibits good discrimination of other DNA conformations, is still needed.…”

Section: Discussionmentioning

confidence: 99%

Characterization of an In Vivo Z-DNA Detection Probe Based on a Cell Nucleus Accumulating Intrabody

et al. 2016

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Left-handed Z-DNA is a physiologically unstable DNA conformation, and its existence in vivo can be attributed to localized torsional distress. Despite evidence for the existence of Z-DNA in vivo, its precise role in the control of gene expression is not fully understood. Here, an in vivo probe based on an anti-Z-DNA intrabody is proposed for native Z-DNA detection. The probe was used for chromatin immunoprecipitation of potential Z-DNA-forming sequences in the human genome. One of the isolated putative Z-DNA-forming sequences was cloned upstream of a reporter gene expression cassette under control of the CMV promoter. The reporter gene encoded an antibody fragment fused to GFP. Transient co-transfection of this vector along with the Z-probe coding vector improved reporter gene expression. This improvement was demonstrated by measuring reporter gene mRNA and protein levels and the amount of fluorescence in co-transfected CHO-K1 cells. These results suggest that the presence of the anti-Z-DNA intrabody can interfere with a Z-DNA-containing reporter gene expression. Therefore, this in vivo probe for the detection of Z-DNA could be used for global correlation of Z-DNA-forming sequences and gene expression regulation.

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“…The Z–domain of ADAR1 has also recently been reported to bind the G-quadruplex of the c-Myc promoter (132) and NMR studies indicate that the mode of interaction is likely to be similar to the interaction of the Zα-domain of Z-DNA and Z-RNA.…”

Section: Other Dna and Rna Binding Proteins (Drbps)mentioning

confidence: 95%

Structure-specific nucleic acid recognition by L-motifs and their diverse roles in expression and regulation of the genome

Thapar

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The high-mobility group (HMG) domain containing proteins regulate transcription, DNA replication and recombination. They adopt L-shaped folds and are structure-specific DNA binding motifs. Here, I define the L-motif super-family that consists of DNA-binding HMG-box proteins and the L-motif of the histone mRNA binding domain of Stem-Loop Binding Protein (SLBP). The SLBP L-motif and HMG-box domains adopt similar L-shaped folds with three α-helices and two or three small hydrophobic cores that stabilize the overall fold, but have very different and distinct modes of nucleic acid recognition. A comparison of the structure, dynamics, protein-protein and nucleic acid interactions, and regulation by PTMs of the SLBP and the HMG-box L-motifs reveals the versatile and diverse modes by which L-motifs utilize their surfaces for structure-specific recognition of nucleic acids to regulate gene expression.

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Novel Interaction of the Z-DNA Binding Domain of Human ADAR1 with the Oncogenic c-Myc Promoter G-Quadruplex

Cited by 30 publications

References 57 publications

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Characterization of an In Vivo Z-DNA Detection Probe Based on a Cell Nucleus Accumulating Intrabody

Structure-specific nucleic acid recognition by L-motifs and their diverse roles in expression and regulation of the genome

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