How does the ATPase motor shift DNA past the histone core?

A basic property for many types of chromatin remodelers is their ability to shift duplex DNA past the histone core, resulting in nucleosome repositioning. Although great strides have been made over the last decade, how remodelers move nucleosomes is poorly understood.

Nucleosome repositioning is powered by a helicase-type superfamily 2 (SF2) ATPase motor that can translocate along DNA (Lia et al., 2006). Several distinct models for nucleosome sliding have been proposed (reviewed in (Bowman, 2010), but recent single-molecule data strongly supporting twist-diffusion as a basic mechanism for repositioning. The twist-diffusion model (van Holde, 2003) postulates that DNA shifts discontinuously past each histone contact in small or single base pair (bp) steps.

twist diffusion model
The Twist-Diffusion model for nucleosome sliding.

As observed with the first nucleosome crystal structure and other subsequent structures, certain segments of nucleosomal DNA can tolerate single bp insertions or deletions between minor groove contacts (Luger et al., 1997). The idea of twist-diffusion is that if one segment of DNA bounded by minor groove contacts could maintain energetically similar histone interactions despite gaining or lacking one bp, such a “distortion” could be propagated from one DNA segment to the next around the nucleosome, resulting in translocation of DNA relative to the histone core. Strong support for this model was provided by two high-resolution single molecule FRET (smFRET) studies, which demonstrated that ISWI and RSC remodelers shift DNA past the histone core in single bp steps (Deindl et al., 2013; Harada et al., 2016).

While repositioning in single bp steps is consistent with a helicase-like DNA translocase motor, what has been perplexing is the apparent ability of ISWI remodelers to distort DNA on the nucleosome (Deindl et al., 2013). Using single-stranded DNA gaps to block DNA translocation at specific locations, it was shown that ISWI remodelers could shift up to 8 bp off the exit side of the nucleosome before any DNA had been pulled onto the histone core from the entry side. This result suggests that DNA is somehow stretched on the nucleosome. In agreement with the idea that remodelers can stretch DNA like a spring, after transient shifts of <8 bp off the histone core, exit DNA was shown to rapidly shift back to the starting position if further translocation was blocked by single stranded gaps (Deindl et al., 2013) or by using a partially disrupted remodeler (Hota et al., 2013). This recoiling back to its starting position is consistent with a spring-like stretching of DNA by the remodeler, yet the details of how DNA may be altered by remodelers, and how such a potential distortion may contribute to repositioning is currently not known. Given the high degree of structural and sequence similarity, we will use Chd1 as a model system for probing where and how a remodeler ATPase motor could affect the structure and properties of nucleosomal DNA.

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