Dataset Information

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators.

ABSTRACT: Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4, and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease, and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET family proteins regulate gene expression are not well defined. In particular, the functions of the other domains such as the ET domain have been less extensively studied. Here, we examine the properties of the ET domain of BRD3 as a protein/protein interaction module. Using a combination of pulldown and biophysical assays, we demonstrate that BRD3 binds to a range of chromatin-remodeling complexes, including the NuRD, BAF, and INO80 complexes, via a short linear "KIKL" motif in one of the complex subunits. NMR-based structural analysis revealed that, surprisingly, this mode of interaction is shared by the AF9 and ENL transcriptional coregulators that contain an acetyl-lysine-binding YEATS domain and regulate transcriptional elongation. This observation establishes a functional commonality between these two families of cancer-related transcriptional regulators. In summary, our data provide insight into the mechanisms by which BET family proteins might link chromatin acetylation to transcriptional outcomes and uncover an unexpected functional similarity between BET and YEATS family proteins.

SUBMITTER: Wai DCC

PROVIDER: S-EPMC5949996 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators.

Wai Dorothy C C DCC Szyszka Taylor N TN Campbell Amy E AE Kwong Cherry C Wilkinson-White Lorna E LE Silva Ana P G APG Low Jason K K JKK Kwan Ann H AH Gamsjaeger Roland R Chalmers James D JD Patrick Wayne M WM Lu Bin B Vakoc Christopher R CR Blobel Gerd A GA Mackay Joel P JP

The Journal of biological chemistry 20180322 19

Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4, and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease, and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer. However, although it is clear that these proteins use their bromodomains to bind both histones and transcriptio ...[more]

PMID: 29567837

Similar Datasets

Project description:The precise placement of nucleosomes has large regulatory effects on gene expression. Recent work suggests that nucleosome placement is regulated in part by the affinity of the underlying DNA sequence for the histone octamer. Nucleosome locations are also regulated by several different ATP-dependent chromatin remodeling enzymes. This raises the question of whether DNA sequence influences the activity of chromatin remodeling enzymes. DNA sequence could most simply regulate nucleosome remodeling through its effect on nucleosome stability. In such a model, unstable nucleosomes would be remodeled faster than stable nucleosomes. It is also possible that certain DNA elements could regulate remodeling by inhibiting the interaction of nucleosomes with the remodeling enzyme. A third possibility is that DNA sequence could regulate the outcome of remodeling by influencing how reaction intermediates collapse into a particular set of stable nucleosomal positions. Here we dissect the contribution from these potential mechanisms to the activities of yeast RSC and human ACF, which are representative members of two major classes of remodeling complexes. We find that varying the histone-DNA affinity over 3 orders of magnitude has negligible effects on the rates of nucleosome remodeling and ATP hydrolysis by these two enzymes. This suggests that the rate-limiting step for nucleosome remodeling may not involve the disruption of histone-DNA contacts. We further find that a specific curved DNA element previously hypothesized to inhibit ACF activity does not inhibit substrate binding or remodeling by ACF. The element, however, does influence the distribution of nucleosome positions generated by ACF. Our data support a model in which remodeling enzymes move nucleosomes to new locations by a general sequence-independent mechanism. However, consequent to the rate-limiting remodeling step, the local DNA sequence promotes a collapse of remodeling intermediates into highly resolved positions that are dictated by thermodynamic differences between adjacent positions.

Dataset Information

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators.

Publications

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets