Priming the nucleosome: a role for HMGB proteins?

Abstract

The high-mobility-group B (HMGB) chromosomal proteins are characterized by the HMG box, a DNA-binding domain that both introduces a tight bend into DNA and binds preferentially to a variety of distorted DNA structures. The HMGB proteins seem to act primarily as architectural facilitators in the manipulation of nucleoprotein complexes; for example, in the assembly of complexes involved in recombination and transcription. Recent genetic and biochemical evidence suggests that these proteins can facilitate nucleosome remodelling. One mechanism by which HMGB proteins could prime the nucleosome for migration is to loosen the wrapped DNA and so enhance accessibility to chromatin-remodelling complexes and possibly also to transcription factors. By constraining a tight loop of untwisted DNA at the edge of a nucleosome, an HMGB protein could induce movements in the contacts between certain core histones that would result in an overall change in nucleosome structure.

Figure 1

Proposed mechanism for transient unwrapping of histone-bound DNA and transcription factor binding (adapted from Widom, 2001). Stochastic unwrapping of DNA from one exit/entry point (E) can result in the exposure of a binding site (white box) for a sequencespecific DNA-binding protein. This model suggests one mechanism by which HMGB proteins (blue) might facilitate transcription factor (TF) binding. X indicates the nucleosome dyad.

Figure 2

Proposed simultaneous interaction of a single high mobility group (HMG)-box HMGB protein with the histone octamer and associated DNA. The HMG domain binds on the outside of the DNA bend while the basic region neutralizes the negative charges on the DNA inside the bend. The positively charged acidic tail binds to negative charges on the histone octamer.

Figure 3

Proposed mechanism for priming nucleosomes by HMGB proteins. A, In an intact nucleosome the DNA is tightly wrapped, entering and leaving the structure at sites marked E. The dyad (X), or midpoint, is at the centre of the wrapped DNA. Histone H2A/H2B dimers and H3/H4 dimers are indicated in green and blue, respectively. B, Binding of an HMGB protein just outside one exit/entry point creates an untwisted bend in the DNA that alters the nucleosome structure. C, Previously inaccessible regions are exposed, which are potentially accessible to (D) transcription factors (TF) or to (E) chromatin remodelling complexes (RC). F, When associated with RNA polymerase II (as the FACT/SPN complex), the HMG-induced destabilization of nucleosomal structure could result in the dissociation of an H2A/H2B dimer (Kireeva et al., 2002).

Figure 4

A general model for the function of HMGB proteins. An HMGB protein bound in the vicinity of an exit/entry point induces increased access to both DNA gyres in a spatially restricted patch. Elsewhere the HMGB protein lessens accessibility. The alternative, less accessible conformation of the nucleosome is stabilized by histone H1. Accessible and bound segments of DNA are indicated in orange and red, respectively.