scholarly journals Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefanie Schöne ◽  
Marcel Jurk ◽  
Mahdi Bagherpoor Helabad ◽  
Iris Dror ◽  
Isabelle Lebars ◽  
...  
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Binding Site ◽  
Structural Changes ◽  
Target Genes ◽  
Quaternary Structure ◽  
Dimensional Structure ◽  
Genomic Context ◽  
The Core ◽  
Induced Changes

Abstract The glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes.

scholarly journals Determinants for DNA-binding site recognition by the glucocorticoid receptor.

1992 ◽  
Vol 267 (35) ◽  
pp. 24941-24947
Author(s):  
J Zilliacus ◽  
A.P. Wright ◽  
U Norinder ◽  
J.A. Gustafsson ◽  
J Carlstedt-Duke
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Binding Site ◽  
Dna Binding Site ◽  
Site Recognition

scholarly journals Correction: Corrigendum: Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefanie Schöne ◽  
Marcel Jurk ◽  
Mahdi Bagherpoor Helabad ◽  
Iris Dror ◽  
Isabelle Lebars ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Binding Site ◽  
The Core ◽  
Receptor Structure ◽  
Structure And Activity

scholarly journals Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

2016 ◽  
Vol 113 (16) ◽  
pp. 4326-4331 ◽  
Author(s):  
Anja Reintjes ◽  
Julian E. Fuchs ◽  
Leopold Kremser ◽  
Herbert H. Lindner ◽  
Klaus R. Liedl ◽  
...  
Keyword(s):  
Dna Binding ◽  
Stress Responses ◽  
Structural Changes ◽  
Target Genes ◽  
Direct Interaction ◽  
Type I ◽  
Critical Residue ◽  
The Stability ◽  
Dynamics Simulations ◽  
Protein Arginine Methyltransferase 1

Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB–activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA–NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.

scholarly journals SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site

2017 ◽  
Author(s):  
Liyang Zhang ◽  
Gabriella D. Martini ◽  
H. Tomas Rube ◽  
Judith F. Kribelbauer ◽  
Chaitanya Rastogi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Target Genes ◽  
Isothermal Calorimetry ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Relative Preference ◽  
Wide Range ◽  
Two Factors ◽  
Prostate Cancers

ABSTRACTThe DNA-binding interfaces of the androgen (AR) and glucocorticoid (GR) receptors are virtually identical, yet these transcription factors share only about a third of their genomic binding sites and regulate similarly distinct sets of target genes. To address this paradox, we determined the intrinsic specificities of the AR and GR DNA binding domains using a refined version of SELEX-seq. We developed an algorithm, SelexGLM, that quantifies binding specificity over a large (31 bp) binding-site by iteratively fitting a feature-based generalized linear model to SELEX probe counts. This analysis revealed that the DNA binding preferences of AR and GR homodimers differ significantly, both within and outside the 15bp core binding site. The relative preference between the two factors can be tuned over a wide range by changing the DNA sequence, with AR more sensitive to sequence changes than GR. The specificity of AR extends to the regions flanking the core 15bp site, where isothermal calorimetry measurements reveal that affinity is augmented by enthalpy-driven readout of poly-A sequences associated with narrowed minor groove width. We conclude that the increased specificity of AR is correlated with more enthalpy-driven binding than GR. The binding models help explain differences in AR and GR genomic binding, and provide a biophysical rationale for how promiscuous binding by GR allows functional substitution for AR in some castration-resistant prostate cancers.

scholarly journals Identification of potential target genes for Adr1p through characterization of essential nucleotides in UAS1.

1994 ◽  
Vol 14 (6) ◽  
pp. 3842-3852 ◽  
Author(s):  
C Cheng ◽  
N Kacherovsky ◽  
K M Dombek ◽  
S Camier ◽  
S K Thukral ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Inverted Repeat ◽  
Target Genes ◽  
Consensus Sequence ◽  
Regulatory Protein ◽  
Yeast Saccharomyces Cerevisiae ◽  
Amino Terminal ◽  
Potential Target

Adr1p is a regulatory protein in the yeast Saccharomyces cerevisiae that binds to and activates transcription from two sites in a perfect 22-bp inverted repeat, UAS1, in the ADH2 promoter. Binding requires two C2H2 zinc fingers and a region amino terminal to the fingers. The importance for DNA binding of each position within UAS1 was deduced from two types of assays. Both methods led to an identical consensus sequence containing only four essential base pairs: GG(A/G)G. The preferred sequence, TTGG(A/G)GA, is found in both halves of the inverted repeat. The region of Adr1p amino terminal to the fingers is important for phosphate contacts in the central region of UAS1. However, no base-specific contacts in this portion of UAS1 are important for DNA binding or for ADR1-dependent transcription in vivo. When the central 6 bp were deleted, only a single monomer of Adr1p was able to bind in vitro and activation in vivo was severely reduced. On the basis of these results and previous knowledge about the DNA binding site requirements, including constraints on the spacing and orientation of sites that affect activation in vivo, a consensus binding site for Adr1p was derived. By using this consensus site, potential Adr1p binding sites were located in the promoters of genes known to show ADR1-dependent expression. In addition, this consensus allowed the identification of new potential target genes for Adr1p.

scholarly journals t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1392-1401 ◽  
Author(s):  
Akiko J. Okumura ◽  
Luke F. Peterson ◽  
Fumihiko Okumura ◽  
Anita Boyapati ◽  
Dong-Er Zhang
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Site ◽  
Dna Sequences ◽  
Fusion Proteins ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromosome Abnormalities ◽  
Cancer Development ◽  
Dna Binding Site

AbstractChromosome abnormalities are frequently associated with cancer development. The 8;21(q22;q22) chromosomal translocation is one of the most common chromosome abnormalities identified in leukemia. It generates fusion proteins between AML1 and ETO. Since AML1 is a well-defined DNA-binding protein, AML1-ETO fusion proteins have been recognized as DNA-binding proteins interacting with the same consensus DNA-binding site as AML1. The alteration of AML1 target gene expression due to the presence of AML1-ETO is related to the development of leukemia. Here, using a 25-bp random double-stranded oligonucleotide library and a polymerase chain reaction (PCR)-based DNA-binding site screen, we show that compared with native AML1, AML1-ETO fusion proteins preferentially bind to DNA sequences with duplicated AML1 consensus sites. This finding is further confirmed by both in vitro and in vivo DNA-protein interaction assays. These results suggest that AML1-ETO fusion proteins have a selective preference for certain AML1 target genes that contain multimerized AML1 consensus sites in their regulatory elements. Such selected regulation provides an important molecular mechanism for the dysregulation of gene expression during cancer development.

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