Duality in Bromodomain-Containing Protein ComplexesGerald V. Denis Cancer Research Center, Boston University School of Medicine, Room K520, 72 East Concord Street, Boston, MA, USA 02118AbstractProteins that contain a motif called a bromodomain are implicated in both transcriptional activation and repression. The bromodomain of p/CAF, the only solution structure of a bromodomain that has been solved to date, reveals that the motif binds N-acetyl-lysine groups, presumably to anchor enzymatic functions to histones and by extension to chromatin. The enzymatic activities can either be encoded within the same polypeptide as the bromodomain motif, or associated with a multiprotein complex. Thus, a wide variety of chromatin-directed functions, including but not limited to phosphorylation, acetylation, methylation, transcriptional co- activation or recruitment, characterize the complexes that contain bromodomain motifs. Their versatility and ubiquity ensures diverse, rapid and flexible transcriptional responses.KeywordsBromodomain; Chromatin; Transcription Regulation; SWI/SNF; Histone Acetyltransferase; Cell Cycle2. TRANSCRIPTIONAL ACTIVATION AND REPRESSIONThe field of chromatin structure has experienced an explosion of interest recently, with almost 2000 Medline citations on the subject in the last two years. Many contemporary reports have focused attention on the causal links between specific modifications of histones, such as N-lysyl-acetylation or deacetylation, and the resultant loosening or tightening of nucleosome structure and consequent transcriptional activation or repression of genes. These local shifts are connected to global changes in cell physiology, such as growth and mitosis. The field has been extensively reviewed of late (17). Moreover, the relationship between different types of histone modification has garnered notice, particularly the observation that phosphorylation of serine-10 and acetylation of lysine-14 on histone H3 are coupled processes with important biological consequences (8,9). In mammalian cells, histone H3 phosphorylation has been identified as a key step both in rapid responses to growth factor stimulation (10,11), resulting in transactivation of “immediate-early” type genes such as c-fos and c-myc (12), as well as much later in chromatin condensation during mitosis (13). An expansive view of the chromatin landscape has come from investigation ofSend correspondence to: Gerald V. Denis, Ph. D., Cancer Research Center, Room K520, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA, Tel: 6174141371, Fax: 6176385673, gdenisbu.edu. Publishers Disclaimer: This is an un-copyedited, author manuscript that has been accepted for publication in the Frontiers in Bioscience, with citation: Frontiers in Bioscience 6, d849-852, August 1, 2001. This article may not be duplicated or reproduced, other than for personal use or within the rule of “Fair Use of Copyrighted Materials” (section 107, Title 17, U.S. Code) without permission of the copyright holder, the Frontiers in Bioscience. From the time of acceptance following peer review, the full final copy edited article of this manuscript will be made available at http:/www.bioscience.org/. The Frontiers in Bioscience disclaims any responsibility or liability for errors or omissions in this version of the un-copyedited manuscript or in any version derived from it by the National Institutes of Health or other parties.NIH Public Access Author Manuscript Front Biosci. Author manuscript; available in PMC 2011 February 7.Published in final edited form as: Front Biosci. ; 6: D849D852.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptthe genetics and biochemistry of chromatin remodeling complexes: large, multisubunit catalytic entities perform the work of histone modification that leads either to transcriptional activation or repression of target genes. Here, promoter selectivity for sequence-specific DNA binding proteins must guide the assembly of these big chromatin-modifying machines, yet the genetic regulatory elements must also be able to respond rapidly to changing transcriptional requirements. Active investigation of chromatin remodeling continues in many laboratories, from the level of sequence-specific modification of specific histones to the level of multiprotein complex assembly.A particular protein motif called a “bromodomain” has been noticed in many of the proteins that compose the chromatin modifying machinery. It was first identified in 1992 as a 61 63 amino acid signature (14). Although it lacked a known function at the time, it has subsequently been identified in transcription factors, co-activators and other proteins that are important in transcription or chromatin remodeling and its boundaries have been expanded to about 110 amino acids. The number of such proteins was about forty at last report (15,16) and several important additions to the family have been made since th