Mechanisms of ATP-dependent nucleosome sliding

Abstract

Chromatin remodelers are multifunctional protein machines that use a conserved ATPase motor to slide nucleosomes along DNA. Nucleosome sliding has been proposed to occur through two mechanisms: twist diffusion and loop/bulge propagation. A central idea for both of these models is that a DNA distortion propagates over the surface of the nucleosome. Recent data from biochemical and single-molecule experiments have expanded our understanding of histone-DNA and remodeler-nucleosome interactions, and called into question some of the basic assumptions on which these models were originally based. Advantages and challenges of several nucleosome sliding models are discussed.

FIGURE 1

Two current models for nucleosome sliding. (a) The twist diffusion model [–5]. In this model, a segment of DNA at the entry/exit site of the nucleosome releases or absorbs a single base pair from the linker DNA. In the figure, an additional base pair is inserted from the left. This distortion is predicted to be relatively minor and thus not disrupt histone-DNA contacts. Transfer of this twist distortion to a neighboring DNA segment would translocate and rotate the DNA duplex by one base pair relative to the protein. Propagation of such a distortion around the histone core would effectively move the nucleosome along the DNA one basepair at a time, with a full rotation of duplex for every ~10.4 base pairs. (b) The loop/bulge propagation model [–15]. In this model, movement of the histone core along DNA is accomplished by formation of a DNA bulge or loop, which disrupts one or a few histone-DNA contacts. Once such a loop has formed, the region of disruption can shift around the nucleosome in a wave-like propagation, breaking new histone-DNA contacts in front and reforming contacts behind. Movement of such a loop from one end of the nucleosome to the other effectively shifts the histone core by the length of the loop.

FIGURE 2

Energy landscape of histone-DNA interactions as determined by single molecule unzipping [””]. Above, a slice through the nucleosome separately depicting each half of the 146 base pair DNA segment wrapped around the histone core. Locations where the DNA minor groove contacts the histone core are highlighted with colored dots. Below, a histone-DNA interaction map calculated from unzipping mononucleosomes in the forward (black) and reverse (red) directions. DNA was unzipped at a constant force of ~28 pN, with the dwell time reporting on the relative strengths of each histone-DNA interaction. In this experiment the strength of histone-DNA contacts cannot be measured past the dyad due to octamer dissociation. Note the dominance of SHL±0.5 contacts around the dyad, and the relative weakness of the contacts at SHL±2.5. Adapted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology [23], 2009.

FIGURE 3

A summary of remodeler-nucleosome interactions. (a) Iswi-nucleosome interactions. Regions of nucleosomal DNA protected by the yeast Isw2 complex from hydroxyl radical cleavage [38] are indicated by red spheres. Positions where single nucleotide gaps interfered with mononucleosome sliding are shown in green, whereas those that did not affect sliding are shown in black [””]. In the sliding reaction, DNA from the linker is shifted onto the histone core, which means that the DNA bound by the ATPase motor (at SHL2) shifts towards the dyad. (b) A model of the RSC remodeler bound to a nucleosome [36]. Cryo-EM reconstructions show that the RSC remodeler possesses a large central cavity capable of engulfing a single nucleosome. A nucleosome is shown modeled into this central cavity such that the dyad and entry/exit DNA segments remain exposed. Images adapted with permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology [12], 2006; and [36], Copyright (2007) National Academy of Sciences, U.S.A.

FIGURE 4

A general model for nucleosome sliding based on swiveling of the histone core. (a) In this model, the action of a remodeler ATPase motor around SHL2 changes the structure of DNA (yellow) which in turn alters the landscape of histone-DNA contacts in this region. These changes make it more favorable for the energetically important contacts around the dyad (indicated by the vertical black arrow) to shift towards the remodeler, accomplished by a swiveling of the histone core within the outer wrapping of DNA. This swiveling will allow the histone core to shift register by one minor groove, effectively translocating the nucleosome along DNA while still maintaining DNA rotational phasing. (b) The DNA-binding surface of the histone core is covered with basic residues that may assist in swiveling of the histone octamer. The side chains for all lysine and arginine residues within 7 Å of DNA are shown as spheres ([6]; pdb code 1AOI). The high density of basic residues may allow the histone core to swivel between minor groove registers by stabilizing the wrapped organization of DNA. In addition to the single arginine residues that partially intercalate in the minor grooves (magenta), each minor groove is accompanied by two or more basic residues that could contact the DNA backbone if the DNA shifted off of the α1-α1 and L1–L2 contacts.