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The eukaryotic abundant high mobility group HMGA and HMGB proteins can act as architectural transcription factors by promoting the assembly of higher-order protein-DNA complexes which can either activate or repress gene expression. The structural organisation of both classes of protein is similar with either a single or repeated DNA binding domain preceding a short negatively charged C-terminal tail. In the HMGB class of proteins the HMG DNA-binding domain binds non-specifically and introduces a sharp bend into DNA whereas the AT-hook in the HMGA protein binds preferentially to A/T rich regions of DNA and stabilises a B-DNA structure. The acidic tails are hypothesised to facilitate the interaction of the proteins with nudeosomes by binding to the positively charged histone tails. Both classes of protein also interact with a large number of transcription factors that bind to specific DNA sequences.

The human testis-determining gene , a single-copy gene on the short arm of the Y chromosome, encodes a high-mobility-group (HMG) box, a DNA-bending motif conserved among architectural transcription factors. The SRY-DNA complex exhibits a dramatic reorganization of the double helix. Although -related genes are of broad interest in relation to development, the mechanistic role of SRY in gene regulation has remained enigmatic. It is not known whether the HMG box is the sole functional domain of the protein. Additional unresolved issues include identification of target genes and interacting proteins. Although sex-reversal mutations commonly impair DNA binding, this correlation is not rigorous and does not exclude alternative regulatory mechanisms, such as possible SRY-directed RNA splicing. New studies of transgenic XX mice expressing chimeric SRY proteins suggest a powerful methodology to investigate structure-function relationships. Progress may benefit from genetic, genomic- and proteomic-based technologies to delineate the downstream pathway of SRY.

The structural and mechanical properties of DNA influence nudeosome positioning and the manner in which DNA is organized in chromatin. Curved DNA structures, poly(dA·dT) sequences, and Z-DNA-forming sequences frequently occur near transcription start sites. Many reports have indicated that curved DNA structures play an important role in the formation, stability and positioning of nucleosomes, and consequently in DNA packaging in nuclei. Curved DNA structures and poly(dA·dT) sequences can increase the accessibility of target DNA elements of activators in chromatin to facilitate initiation of transcription. Z-DNA seems to be implicated in gene activation coupled with chromatin remodeling, and eukaryotes may use triplex DNA and cruciform structures to manipulate chromatin structure in a site-specific manner.

The placement of nucleosomes along genomic DNA is determined by signals that can be specific or degenerate at the level of sequence; the latter signals are harder to find using conventional methods. In recent years, the development of sophisticated machine learning techniques that can extract subtle phased signals has improved our ability to distinguish between various classes of nucleosome-positioning sequences. Our knowledge of the structural mechanics of free DNA also has reached the point where it can be fruitfully incorporated into predictive models. More importantly, the accumulation of high-resolution structures with proteins bound to DNA, and those of nucleosomes in particular, has provided important clues about the role of DNA bending and flexibility in nudeosome positioning.