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• W1978573663 abstract "Control of gene expression depends on a myriad of protein-DNA interactions, and the number of proteins involved just got larger. In this issue, Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar identify hundreds of human proteins that bind to DNA, including many surprises such as the protein kinase ERK2 (MAPK1) that now appears to control gene expression directly. Control of gene expression depends on a myriad of protein-DNA interactions, and the number of proteins involved just got larger. In this issue, Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar identify hundreds of human proteins that bind to DNA, including many surprises such as the protein kinase ERK2 (MAPK1) that now appears to control gene expression directly. Cells respond to changes in their environment with changes in gene expression. Signal transduction pathways make this happen as they transmit external cues from the cell surface to the nucleus. Transcription is regulated by the interplay of DNA cis-regulatory sequences and trans-acting factors. Although many classes of transcription factors have been well-studied, high-throughput approaches including chromatin immunoprecipitation (ChIP), microarrays, and deep sequencing have accelerated the discovery of novel protein-DNA interactions across genomes creating new frontiers and challenges for understanding control of gene expression. Through a DNA-binding analysis of an array of more than 4000 recombinant proteins, Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar reporting in this issue now expand the set of human proteins known to bind to DNA directly, offering a fresh perspective on sequence-specific transcription factors. Beyond the expected classes of transcription factors, the authors discovered new DNA-protein interactions involving unconventional DNA-binding proteins (uDBPs), such as the protein kinase ERK2 (MAPK1), that may alter gene expression directly by interacting with DNA. Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar come at the challenge of finding protein-DNA interactions from the flip side of many DNA-centric studies looking at transcription factor binding. They focus on the proteins, “printing” recombinant proteins onto arrays and probing for the DNA sequences that bind to them. They benchmark the approach by looking at known DNA-binding proteins. Consensus sequences were identified for more than 200 transcription factors, including canonical binding sites for uncharacterized, but suspected factors, such as members of the zf-C2H2 subfamily. Surprisingly, the authors find that more than 300 uDBPs, including ERK2, bind to DNA in a sequence-specific manner. Through bioinformatics the authors predict that uDBPs account for more than 20% of the proteins encoded in the genome. Despite the abundance of uDBPs identified, even more are expected from protein classes that were excluded from the analysis (e.g., heterodimers, and proteins not known to be located in the nucleus). Given the array analysis, it is conceivable that the uDBPs may simply represent proteins with the adventitious ability to associate with DNA when taken out of their cellular context. Bolstering the case for the specificity of these interactions, the authors go on to characterize a subset of proteins in vitro and in vivo. They find, for instance, that the DNA consensus sequence G/CAAAG/C interacts directly with recombinant ERK2 in vitro and confers ERK2-dependent repression of luciferase reporter gene expression. Importantly, mutations in the protein sequence abrogate the interaction with DNA and transcriptional repression does not depend on ERK2's kinase activity. In search of an endogenous role for ERK2-mediated repression of transcription, Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar knock down the protein and look at the consequences for gene expression. Of 82 genes whose expression increases following siRNA-mediated ERK2 knockdown, 78 harbor one or more ERK2-binding consensus motifs and roughly half are projected to bind to ERK2 based on ChIP analysis. The evidence is consistent with ERK2 acting directly as a transcriptional repressor, but future studies will be needed to forge a mechanistic link between gene repression and ERK2 sequence-specific binding to DNA. A fraction of gene expression changes may instead be mediated through ERK2 substrates. ERK2 and its close relative the kinase ERK1 have nearly overlapping functions and both are expressed in the HeLa cells studied, suggesting that ERK1 also may bind to DNA. MAPKs are known to influence gene expression through several established mechanisms. For example, phosphorylation can modulate transcriptional components as in the case of the ternary complex factor Elk-1, which, when phosphorylated by ERK2, boosts transcription of genes like c-fos with serum response elements in their promoters (Gille et al., 1992Gille H. Sharrocks A.D. Shaw P.E. Nature. 1992; 358: 414-416Crossref PubMed Scopus (799) Google Scholar). Activated ERK2, ERK1, as well as p38 MAPK can bind to chromatin (Lawrence et al., 2008Lawrence M.C. McGlynn K. Shao C. Duan L. Naziruddin B. Levy M.F. Cobb M.H. Proc. Natl. Acad. Sci. USA. 2008; 105: 13315-13320Crossref PubMed Scopus (54) Google Scholar, Pokholok et al., 2006Pokholok D.K. Zeitlinger J. Hannett N.M. Reynolds D.B. Young R.A. Science. 2006; 313: 533-536Crossref PubMed Scopus (197) Google Scholar), and the substrates of these kinases can directly phosphorylate histones (Edmunds and Mahadevan, 2004Edmunds J.W. Mahadevan L.C. J. Cell Sci. 2004; 117: 3715-3723Crossref PubMed Scopus (92) Google Scholar). However, blocking kinase activity prevents the transcriptional activity of these kinases, suggesting that the new direct transcriptional role described by Hu et al. is distinct. To explore a biological context for ERK2-mediated gene repression in cells, Hu et al., 2009Hu S. Xie Z. Onishi A. Yu X. Jiang L. Lin J. Rho H.S. Woodard C. Wang H. Jeong J.-S. et al.Cell. 2009; (this issue)Google Scholar studied a subset of the ERK2-repressed genes that overlaps with a set of genes induced by interferon γ (IFNγ). They measured recruitment of ERK2 to the promoters of two genes, OAS1 and IRF9, involved in the IFNγ-induced immune response to viral infection. These promoters contain a conserved IFNγ-activated transcriptional DNA element (GATE) that is bound by the transcription factor C/EBP-β. An ERK2 binding consensus sequence is embedded within the GATE element. The conclusions of the current study suggest that ERK2 and C/EBP-β may compete for binding to this element. Although some data support this model, further work is needed to establish whether the proteins do in fact compete and if they do whether this interplay has functional consequences. Upon activation by IFNγ, ERK2, ERK1, and RSK phosphorylate C/EBP-β, increasing its activity via enhanced binding to GATE and to the large transcriptional complex Mediator. This substrate-dependent mechanism could also account for the observed IFNγ-dependent induction of mRNAs from OAS1 and IRF9. Hu et al. take advantage of structural information about ERK2 to design DNA-binding defective mutant proteins. The key residues (K259 and R261) for DNA binding in ERK2 are in a region called the MAPK insert, and when either of these residues is mutated ERK2 does not bind to DNA to repress transcription (Figure 1). In the presence or absence of activating ligands, ERK2 and ERK1 bind to nuclear pore proteins enabling them to move in and out of the nucleus (Yazicioglu et al., 2007Yazicioglu M.N. Goad D. Ranganathan A. Whitehurst A.W. Goldsmith E.J. Cobb M.H. J. Biol. Chem. 2007; 282: 28759-28767Crossref PubMed Scopus (48) Google Scholar), consistent with the fact that inactive ERK2 is in the nucleus and can repress transcription. The MAPK insert is also required for binding of ERK2 to nuclear pore proteins and hence for entry of the inactive protein into the nucleus. Mutation of some residues in the MAPK insert (e.g., tyrosine in Figure 1) or deletion of the insert itself impairs or prevents nuclear entry of the kinase (Yazicioglu et al., 2007Yazicioglu M.N. Goad D. Ranganathan A. Whitehurst A.W. Goldsmith E.J. Cobb M.H. J. Biol. Chem. 2007; 282: 28759-28767Crossref PubMed Scopus (48) Google Scholar). As a consequence, ERK2 mutants that do not bind to DNA in vitro also may not be able to enter the nucleus in vivo as efficiently as wild-type ERK2. Thus, although data demonstrating binding of ERK2 to DNA in vitro are strong, parallel experiments in cells using loss-of-function mutants are not so easily interpreted. Interestingly, the MAPK insert is found not only in MAPKs but also in cyclin-dependent kinases and GSK3. All three of these kinase families can bind to chromatin (Lawrence et al., 2008Lawrence M.C. McGlynn K. Shao C. Duan L. Naziruddin B. Levy M.F. Cobb M.H. Proc. Natl. Acad. Sci. USA. 2008; 105: 13315-13320Crossref PubMed Scopus (54) Google Scholar, Narayanan et al., 2005Narayanan R. Adigun A.A. Edwards D.P. Weigel N.L. Mol. Cell. Biol. 2005; 25: 264-277Crossref PubMed Scopus (91) Google Scholar, Vincent et al., 2008Vincent T. Kukalev A. Andang M. Pettersson R. Percipalle P. Oncogene. 2008; 27: 5254-5259Crossref PubMed Scopus (20) Google Scholar), and thus the MAPK insert should be tested as a potential site for DNA binding in members of these families. Until now no functions have been unequivocally attributed to inactive ERK2 and ERK1. In contrast, Bardwell et al., 1998Bardwell L. Cook J.G. Voora D. Baggott D.M. Martinez A.R. Thorner J. Genes Dev. 1998; 12: 2887-2898Crossref PubMed Scopus (140) Google Scholar found that the inactive yeast MAPK Kss1 represses transcription required for filamentous growth. In view of the work reported here, perhaps a repressive function is a common characteristic of inactive MAPKs, which may bind to DNA with distinct sequence specificities. Perhaps foreshadowing the findings here, HipA, a bacterial kinase that is structurally similar to eukaryotic protein kinases, was recently shown to contact DNA directly in a complex with a transcriptional corepressor (Schumacher et al., 2009Schumacher M.A. Piro K.M. Xu W. Hansen S. Lewis K. Brennan R.G. Science. 2009; 323: 396-401Crossref PubMed Scopus (240) Google Scholar). We are left with the tantalizing idea that if kinases and other signaling molecules bind to the conserved regulatory sequences of target genes, then transcriptional regulation by signaling cascades may occur directly at the level of the genes themselves rather than only indirectly through regulation of trans-acting factors. Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon SignalingHu et al.CellOctober 30, 2009In BriefProtein-DNA interactions (PDIs) mediate a broad range of functions essential for cellular differentiation, function, and survival. However, it is still a daunting task to comprehensively identify and profile sequence-specific PDIs in complex genomes. Here, we have used a combined bioinformatics and protein microarray-based strategy to systematically characterize the human protein-DNA interactome. We identified 17,718 PDIs between 460 DNA motifs predicted to regulate transcription and 4,191 human proteins of various functional classes. Full-Text PDF Open Archive" @default.
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• W1978573663 title "MAP-ping Unconventional Protein-DNA Interactions" @default.
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