Genomic and Biochemical Insights into the Specificity of ETS Transcription Factors

Hollenhorst, Peter C.; McIntosh, Lawrence P.; Graves, Barbara J.

doi:10.1146/annurev.biochem.79.081507.103945

Cited by 440 publications

(529 citation statements)

References 237 publications

(296 reference statements)

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“…Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay.…”

mentioning

confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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nature structural & molecular biology advance online publication a r t i c l e sAlthough undisputable evidence has clearly demonstrated that the nuclear steps of mRNA processing are mechanistically linked to transcription, a conceptual evolution in gene regulation has come with the realization that transcription might also be functionally connected to more remote processes occurring in the cytoplasm, such as mRNA decay 1,2 . Cytoplasmic mRNA decay is initiated by deadenylation, a rate-limiting event during which the poly(A) tail of the transcript is trimmed off by the CCR4-NOT complex, the main deadenylation machinery in eukaryotes 3 . The degradation of specific mRNAs, a key process in the regulation of eukaryotic gene expression, is achieved through the recruitment of the CCR4-NOT complex by sequence-specific RNA-binding proteins (RBPs) or by the microRNA machinery 3,4 . Poly(A)-shortened mRNAs, along with factors involved in the deadenylation, decapping and mRNA-degradation machineries, accumulate in microscopic mRNA-protein complex (mRNP) aggregates called processing bodies (PBs) 5 .The idea of coupling between mRNA synthesis and degradation has recently emerged. Genome-wide expression studies in yeast have shown that mRNA synthesis and decay are mechanistically and functionally coordinated, thus supporting the existence of common molecular effectors [6][7][8][9] . In particular, the CCR4-NOT deadenylation complex was first described as a transcriptional regulator and has been implicated in initiation and elongation by RNA polymerase II 10,11 . More surprisingly, it has also been shown that degradation of yeast mRNAs is determined by cis-acting sequence elements in promoters 12,13 . These findings have led to the concept of mRNA imprinting, in which sequence-specific DNA-binding factors might orchestrate mRNA synthesis and decay. This decay would occur via loading of factors regulating cytoplasmic mRNA degradation onto the transcribing mRNA 14 . However, the identity of these DNA-binding mRNA coordinators is still obscure, and it remains to be tested whether such coupling between transcription and decay also exists in higher eukaryotes. E26 (Ets) proteins, a family of 28 helix-loop-helix transcription factors (TFs) in metazoans, are characterized by a highly conserved DNA-binding ETS domain 15 . Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay. We demonstrate that ERG triggers degradation of mRNAs connected to Aurora signaling by recruiting RBPs and the CCR4-NOT deadenylation complex and that this activity is important fo...

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confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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“…48 These and other interactions, all of which are functionally linked to cell fate specification or the regulation of lineage-specific target genes, have been well reviewed. 49 In recent years, high-throughput microarray and sequencing technologies have elevated investigations of ETS/DNA interactions to the genome-wide level. Detailed information on the localization, sequence characteristics of DNA targets, and associated binding partners is now available for ETS transcription factors in a range of cell types and developmental contexts.…”

Section: Combinatorial Routes To Ets Target Specificitymentioning

confidence: 99%

“…We have been focusing our attention on Ets-1 and PU.1, which are attractive model systems for two reasons. First, they are archetypal representatives of the most phylogenetically most distant classes of ETS proteins, 49 so heterogeneity in their molecular phenotype should directly reflect the selection pressures in their evolutionary paths, even if the biologic basis of these pressures are not necessarily known. Second, these two ETS paralogs bind optimal DNA targets with indistinguishably high affinity, 56 so that heterogeneity between the two homologs that contribute to their DNA binding affinity and specificity would be biologically relevant.…”

Section: A Deeper Look Into Ets/dna Recognitionmentioning

confidence: 99%

“…The established molecular pathophysiology associated with some of these mechanisms are listed. The literature on ETS proteins is vast and this summary is only intended to be illustrative; readers interested in specific aspects or paralogs mentioned in this figure are referred to reviews and studies such as the following: 26,49,51,53,66,[87][88][89][90][91][92][93] Note that auto-inhibition (indicated by the cartoon helix) is not a universal feature of ETS proteins; several paralogs, such as PU.1, are not auto-inhibited. Abbreviations: AML, acute myeloid leukemia; Ca, cancer; cHD, classical Hodgkin's disease; MM, multiple myeloma.…”

Section: Role Of Molecular Hydration In Dna Recognition By Ets Proteinsmentioning

confidence: 99%

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Signatures of DNA target selectivity by ETS transcription factors

Poon

Kim

2017

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The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial interactions with other proteins as well as intrinsic heterogeneity among ETS domains. Emerging evidence suggests molecular hydration as a fundamental feature that defines the intrinsic heterogeneity in DNA target selection and susceptibility to epigenetic DNA modification. This perspective invokes novel hypotheses in the regulation of ETS proteins in physiologic osmotic stress, their pioneering potential in heterochromatin, and the effects of passive and pharmacologic DNA demethylation on ETS regulation.

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“…DNA-binding ETS domain, $1/3 of all ETS factors also contain a PNT domain, 1 which is an ETS-specific member of the widespread family of SAM domains. Although sharing a common core architecture of four a-helices and a fifth small a-or 3 10 -helix, SAM domains exhibit remarkably diverse association states and function in a wide variety of protein-protein and protein-RNA interactions.…”

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The PNT domain from Drosophila pointed‐P2 contains a dynamic N‐terminal helix preceded by a disordered phosphoacceptor sequence

2012

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Pointed-P2, the Drosophila ortholog of human ETS1 and ETS2, is a transcription factor involved in Ras/MAP kinase-regulated gene expression. In addition to a DNA-binding ETS domain, Pointed-P2 contains a PNT (or SAM) domain that serves as a docking module to enhance phosphorylation of an adjacent phosphoacceptor threonine by the ERK2 MAP kinase Rolled. Using NMR chemical shift, 15 N relaxation, and amide hydrogen exchange measurements, we demonstrate that the Pointed-P2 PNT domain contains a dynamic N-terminal helix H0 appended to a core conserved five-helix bundle diagnostic of the SAM domain fold. Neither the secondary structure nor dynamics of the PNT domain is perturbed significantly upon in vitro ERK2 phosphorylation of three threonine residues in a disordered sequence immediately preceding this domain. These data thus confirm that the Drosophila Pointed-P2 PNT domain and phosphoacceptors are highly similar to those of the well-characterized human ETS1 transcription factor. NMR-monitored titrations also revealed that the phosphoacceptors and helix H0, as well as region of the core helical bundle identified previously by mutational analyses as a kinase docking site, are selectively perturbed upon ERK2 binding by Pointed-P2. Based on a homology model derived from the ETS1 PNT domain, helix H0 is predicted to partially occlude the docking interface. Therefore, this dynamic helix must be displaced to allow both docking of the kinase, as well as binding of Mae, a Drosophila protein that negatively regulates Pointed-P2 by competing with the kinase for its docking site.

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Genomic and Biochemical Insights into the Specificity of ETS Transcription Factors

Cited by 440 publications

References 237 publications

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Signatures of DNA target selectivity by ETS transcription factors

The PNT domain from Drosophila pointed‐P2 contains a dynamic N‐terminal helix preceded by a disordered phosphoacceptor sequence

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