Review Targeting chromatin remodelers: Signals and search mechanisms ☆ Fabian Erdel a , Jana Krug a , Gernot Längst b , Karsten Rippe a, ⁎ a Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany b Biochemie III, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany abstract article info Article history: Received 10 April 2011 Received in revised form 2 June 2011 Accepted 6 June 2011 Available online 16 June 2011 Keywords: Chromatin remodeling Nucleosome translocation Histone modifications Diffusion-controlled target location Chromatin remodeling complexes are ATP-driven molecular machines that change chromatin structure by translocating nucleosomes along the DNA, evicting nucleosomes, or changing the nucleosomal histone composition. They are highly abundant in the cell and numerous different complexes exist that display distinct activity patterns. Here we review chromatin-associated signals that are recognized by remodelers. It is discussed how these regulate the remodeling reaction via changing the nucleosome substrate/product binding affinity or the catalytic translocation rate. Finally, we address the question of how chromatin remodelers operate in the cell nucleus to find specifically marked nucleosome substrates via a diffusion driven target location mechanism, and estimate the search times of this process. This article is part of a Special Issue entitled:Snf2/Swi2 ATPase structure and function. © 2011 Elsevier B.V. All rights reserved. 1. Chromatin remodeling in mammalian cells Chromatin remodeling complexes hydrolyze ATP to control nucleosome positioning. They are able to evict nucleosomes and are involved in exchanging canonical core histones with histone variants [1]. Their ability to (re)position nucleosomes plays an important role for regulating gene expression as well as mediating access to the DNA during replication and repair [2–9]. Remodeling complexes typically consist of an ATPase containing motor protein and different accessory proteins [1] (Fig. 1). The ATPase subunits of chromatin remodeling enzymes belong to the SF2 superfamily of helicase-related proteins and contain a common core of two RecA helicase domains [10,11]. These couple ATP hydrolysis to protein conformational changes [12]. Within the SF2 helicase group, most chromatin remodeling enzymes belong to the Snf2 family that can be further divided into several subfamilies [13]. The most prominent ones are SWI/SNF, ISWI, CHD and INO80 [1,13]. However, also proteins from other subfamilies such as the Rad54-like remodeler ATRX appear to play important roles in controlling chromatin organization [14,15]. In addition to the helicase domain, proteins of a given family share other characteristic domains that define their biological functions (Fig. 1A). SWI/SNF members contain a bromodomain, ISWI members contain a HAND-SANT-SLIDE domain, and CHD members contain a double chromodomain. ATPases belonging to the INO80 group are characterized by a “split” helicase, which has a long insertion separating the DExx and HELICc domains [13]. Specific interactions of chromatin remodeling complexes with their modified and unmodified nucleosomal substrates can be established via domains of the ATPase and/or associated subunits (Fig. 1). Interactions with nucleosomes are mediated by the bromodomain (BRD/bromo, acetylated histones), the bromo-associated homology domain (BAH, nucleosomes), the chromodomain (CHD/chromo, methylated histones), the plant homeodomain (PHD, unmodified/acetylated/methylated histone tails, globular domain of histones) or HAND/SANT/SLIDE domains (nucleosomes and nucleosomal DNA) as reviewed previously [1] and discussed in Section 2. While the conserved helicase domains suggest a common remodeling mechanism, the diversity of remodeling complex composition points to a high selectivity with respect to the recognition of specific nucleosomal substrates and to a functional diversity of their activity. Here, we review chromatin-associated signals that are recognized by chromatin remodeling complexes and discuss how these control their activity. The different types of signals and their readout by chromatin remodelers are illustrated for prototypic exam- ples. Furthermore, principles for target search and identification mechanisms of remodelers are discussed. 2. Chromatin binding signals that target chromatin remodelers In the cell the ATP-dependent activity of chromatin remodeling complexes makes an important contribution to position nucleosomes [2,4,5,7,8]. This involves an active regulation of nucleosome localiza- tion in the context of the developmental and metabolic state of the cell via the targeted action of ATP-dependent chromatin remodeling complexes as demonstrated in numerous studies [16–20]. These complexes can read chromatin signals like DNA sequence, structure or methylation, recognize histone modifications, detect the presence of histone variants, and can interact with chromatin-associated proteins such as transcription factors to identify specific target nucleosomes in Biochimica et Biophysica Acta 1809 (2011) 497–508 ☆ This article is part of a Special Issue entitled:Snf2/Swi2 ATPase structure and function. ⁎ Corresponding author. E-mail address: Karsten.Rippe@dkfz.de (K. Rippe). 1874-9399/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagrm.2011.06.005 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm