scholarly journals HDAC inhibitor Givinostat targets DNA-binding of human CGGBP1

2020 ◽  
Author(s):  
Manthan Patel ◽  
Divyesh Patel ◽  
Subhamoy Datta ◽  
Umashankar Singh
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Histone Deacetylases ◽  
Antineoplastic Agent ◽  
Dna Binding Protein ◽  
Dna Interaction ◽  
Cancer Cell Proliferation ◽  
Screening Assay ◽  
Chemical Inhibitors ◽  
Simple Screening

ABSTRACTThe antineoplastic agent Givinostat inhibits histone deacetylases. We present here our finding that the DNA-binding of human CGGBP1 is also inhibited by Givinostat. CGGBP1, a DNA-binding protein, is required for cancer cell proliferation. In our quest to exploit the potential anti-proliferative effects of CGGBP1 inhibition, we have developed a simple screening assay to identify chemical inhibitors of DNA-protein interactions. We have applied this screen for human CGGBP1 on a library of 1685 compounds and found that Givinostat is a direct inhibitor of CGGBP1-DNA interaction. The mechanism of action of Givinostat should thus extend beyond HDACs to include the inhibition of the myriad functions of CGGBP1 that depend on its binding to the DNA.

scholarly journals HDAC inhibitor Givinostat targets DNA-binding of human CGGBP1

2020 ◽  
Author(s):  
Manthan Patel ◽  
Divyesh Patel ◽  
Subhamoy Datta ◽  
Umashankar Singh
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Histone Deacetylases ◽  
Antineoplastic Agent ◽  
Dna Binding Protein ◽  
Dna Interaction ◽  
Cancer Cell Proliferation ◽  
Screening Assay ◽  
Chemical Inhibitors ◽  
Simple Screening

Abstract The antineoplastic agent Givinostat inhibits histone deacetylases. We present here our finding that the DNA-binding of human CGGBP1 is also inhibited by Givinostat. CGGBP1, a DNA-binding protein, is required for cancer cell proliferation. In our quest to exploit the potential anti-proliferative effects of CGGBP1 inhibition, we have developed a simple screening assay to identify chemical inhibitors of DNA-protein interactions. We have applied this screen for human CGGBP1 on a library of 1685 compounds and found that Givinostat is a direct inhibitor of CGGBP1-DNA interaction. The mechanism of action of Givinostat should thus extend beyond HDACs to include the inhibition of the myriad functions of CGGBP1 that depend on its binding to the DNA.

scholarly journals HDAC inhibitor Givinostat targets DNA-binding of human CGGBP1

2020 ◽  
Author(s):  
Manthan Patel ◽  
Divyesh Patel ◽  
Subhamoy Datta ◽  
Umashankar Singh
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Histone Deacetylases ◽  
Antineoplastic Agent ◽  
Dna Binding Protein ◽  
Dna Interaction ◽  
Cancer Cell Proliferation ◽  
Screening Assay ◽  
Chemical Inhibitors ◽  
Simple Screening

Abstract The antineoplastic agent Givinostat inhibits histone deacetylases. We present here our finding that the DNA-binding of human CGGBP1 is also inhibited by Givinostat. CGGBP1, a DNA-binding protein, is required for cancer cell proliferation. In our quest to exploit the potential anti-proliferative effects of CGGBP1 inhibition, we have developed a simple screening assay to identify chemical inhibitors of DNA-protein interactions. We have applied this screen for human CGGBP1 on a library of 1685 compounds and found that Givinostat is a direct inhibitor of CGGBP1-DNA interaction. The mechanism of action of Givinostat should thus extend beyond HDACs to include the inhibition of the myriad functions of CGGBP1 that depend on its binding to the DNA.

A new visible-light-driven photoelectrochemical biosensor for probing DNA–protein interactions

2015 ◽  
Vol 51 (39) ◽  
pp. 8381-8384 ◽  
Author(s):  
Zheng-Yuan Ma ◽  
Yi-Fan Ruan ◽  
Nan Zhang ◽  
Wei-Wei Zhao ◽  
Jing-Juan Xu ◽  
...  
Keyword(s):  
Dna Binding ◽  
Visible Light ◽  
Protein Interactions ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Dna Interaction ◽  
Visible Light Driven ◽  
Photoelectrochemical Biosensor ◽  
Dna Protein Interactions

A novel photoelectrochemical approach was achieved for the detection of a DNA binding protein via the protein–DNA interaction.

scholarly journals Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher R. Horne ◽  
Hariprasad Venugopal ◽  
Santosh Panjikar ◽  
David M. Wood ◽  
Amy Henrickson ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Dna Binding ◽  
Protein Interactions ◽  
Acid Metabolism ◽  
Environmental Changes ◽  
Dna Interaction ◽  
Protein Protein Interactions ◽  
Nutrient Source ◽  
Cryo Electron Microscopy ◽  
Close Proximity

AbstractBacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.

A Proline-Rich Region in the Zeste Protein Essential for Transvection and white Repression by Zeste1

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1865-1874
Author(s):  
Christina Rosen ◽  
Dale Dorsett ◽  
Joseph Jack
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Homologous Chromosome ◽  
Protein Complexes ◽  
Dna Binding Protein ◽  
Polycomb Group ◽  
The Self ◽  
Rich Region ◽  
Interaction Domain ◽  
Proline Rich Region

Abstract The DNA-binding protein encoded by the zeste gene of Drosophila activates transcription and mediates interchromosomal interactions such as transvection. The mutant protein encoded by the zeste1 (z1) allele retains the ability to support transvection, but represses white. Similar to transvection, repression requires Zeste-Zeste protein interactions and a second copy of white, either on the homologous chromosome or adjacent on the same chromosome. We characterized two pseudorevertants of z1 (z1-35 and z1-42) and another zeste mutation (z78c) that represses white. The z1 lesion alters a lysine residue located between the N-terminal DNA-binding domain and the C-terminal hydrophobic repeats involved in Zeste self-interactions. The z78c mutation alters a histidine near the site of the z1 lesion. Both z1 pseudorevertants retain the z1 lesion and alter different prolines in a proline-rich region located between the z1 lesion and the self-interaction domain. The pseudorevertants retain the ability to self-interact, but fail to repress white or support transvection at Ultrabithorax. To account for these observations and evidence indicating that Zeste affects gene expression through Polycomb group (Pc-G) protein complexes that epigenetically maintain chromatin states, we suggest that the regions affected by the z1, z78c, and pseudorevertant lesions mediate interactions between Zeste and the maintenance complexes.

scholarly journals Role of the C-Terminal Binding Protein PXDLS Motif Binding Cleft in Protein Interactions and Transcriptional Repression

2006 ◽  
Vol 26 (21) ◽  
pp. 8202-8213 ◽  
Author(s):  
Kate G. R. Quinlan ◽  
Alexis Verger ◽  
Alister Kwok ◽  
Stella H. Y. Lee ◽  
José Perdomo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Protein Interactions ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Gene Repression ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Binding Cleft ◽  
Partner Proteins

ABSTRACT C-terminal binding proteins (CtBPs) are multifunctional proteins that can mediate gene repression. CtBPs contain a cleft that binds Pro-X-Asp-Leu-Ser (PXDLS) motifs. PXDLS motifs occur in numerous transcription factors and in effectors of gene repression, such as certain histone deacetylases. CtBPs have been depicted as bridging proteins that self-associate and link PXDLS-containing transcription factors to PXDLS-containing chromatin-modifying enzymes. CtBPs also recruit effectors that do not contain recognizable PXDLS motifs. We have investigated the importance of the PXDLS binding cleft to CtBP's interactions with various partner proteins and to its ability to repress transcription. We used CtBP cleft mutant and cleft-filled fusion derivatives to distinguish between partner proteins that bind in the cleft and elsewhere on the CtBP surface. Functional assays demonstrate that CtBP mutants that carry defective clefts retain repression activity when fused to heterologous DNA-binding domains. This result suggests that the cleft is not essential for recruiting effectors. In contrast, when tested in the absence of a fused DNA-binding domain, disruption of the cleft abrogates repression activity. These results demonstrate that the PXDLS binding cleft is functionally important but suggest that it is primarily required for localization of the CtBP complex to promoter-bound transcription factors.

scholarly journals Characterizing protein-DNA binding event subtypes in ChIP-exo data

2018 ◽  
Author(s):  
Naomi Yamada ◽  
William K.M. Lai ◽  
Nina Farrell ◽  
B. Franklin Pugh ◽  
Shaun Mahony
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Regulatory Protein ◽  
Distribution Patterns ◽  
Dna Interaction ◽  
Binding Modes ◽  
Dna Motifs ◽  
Multiple Protein ◽  
Binding Event ◽  
Dna Crosslinking

AbstractMotivationRegulatory proteins associate with the genome either by directly binding cognate DNA motifs or via protein-protein interactions with other regulators. Each recruitment mechanism may be associated with distinct motifs and may also result in distinct characteristic patterns in high-resolution protein-DNA binding assays. For example, the ChIP-exo protocol precisely characterizes protein-DNA crosslinking patterns by combining chromatin immunoprecipitation (ChIP) with 5’ → 3’ exonuclease digestion. Since different regulatory complexes will result in different protein-DNA crosslinking signatures, analysis of ChIP-exo tag enrichment patterns should enable detection of multiple protein-DNA binding modes for a given regulatory protein. However, current ChIP-exo analysis methods either treat all binding events as being of a uniform type or rely on motifs to cluster binding events into subtypes.ResultsTo systematically detect multiple protein-DNA interaction modes in a single ChIP-exo experiment, we introduce the ChIP-exo mixture model (ChExMix). ChExMix probabilistically models the genomic locations and subtype memberships of binding events using both ChIP-exo tag distribution patterns and DNA motifs. We demonstrate that ChExMix achieves accurate detection and classification of binding event subtypes using in silico mixed ChIP-exo data. We further demonstrate the unique analysis abilities of ChExMix using a collection of ChIP-exo experiments that profile the binding of key transcription factors in MCF-7 cells. In these data, ChExMix identifies possible recruitment mechanisms of FoxA1 and ERα, thus demonstrating that ChExMix can effectively stratify ChIP-exo binding events into biologically meaningful subtypes.AvailabilityChExMix is available from https://github.com/seqcode/[email protected]

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