Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
DNA Mechanics, Nucleosome Positioning and p53-DNA Recognition
For many years, it has been assumed that the nucleosome positioning is defined entirely by the energy of DNA deformation (bending and twisting) when it is wrapped around the histone core [see the retrospective review by Trifonov (1) and the accompanying commentaries (2,3); many of the relevant detailed papers are in (4-17)]. However, when the high-resolution NCP crystal structure was solved (18), it became clear that bending of the nucleosomal DNA differs drastically from that in the other protein-DNA complexes. The DNA bending in nucleosome is accompanied by strong lateral displacements of the DNA axis (Slide) that are critical for formation of the DNA superhelical path in nucleosome (19). These severe DNA deformations (denoted Kink-and-Slide), occur as a result of interactions with histone arginines which penetrate the DNA minor groove asymmetrically, so that their side chains are closer to one DNA strand (13).
Recent computer simulations of oligonucleotide duplexes suggest that the sequence-dependent deformability of DNA depends on the imposed constraints that mimic the presence of bound protein. In particular, when the Slide constraints observed in the nucleosome were used, the energy of the Kink-and-Slide deformation increased in the order TA ≤ CA:TG < CG (13). Bending into the minor groove brings the highest increase in the deformation energy of DNA (19). Therefore, selection of the ‘correct’ sequences for the minor-groove bending is likely to be the most critical part in the process of finding the optimal position of nucleosomes on DNA. According to our current understanding (12, 13), the optimal minor-groove bending patterns contain the TA and CA:TG dimers in the pyrimidine-purine context YYRR. Importantly, this sequence preference explains the exceptionally high stability of nucleosomes formed by the “TG repeat” (20) and the “601 sequence” (21) containing numerous TTAG and TTAA fragments, respectively.
In addition to folding in nucleosomes, the DNA Slide is implicated in the sequence-specific recognition of DNA by the tumor suppressor protein p53 (22). The shearing deformation of the DNA axis caused by p53 binding (23-25) is consistent with the Kink-and-Slide conformation described above. Therefore, structural organization of a p53 binding site in chromatin can regulate its affinity to p53 – for example, exposure of the DNA site on the nucleosomal surface would facilitate p53 binding to the response element (26). Our results indicate that there is a complex interplay between the structural codes encrypted in eukaryotic genomes – one code for DNA packaging in chromatin, and the other code for DNA recognition by transcription factors (TFs). The two codes appear to be generally consistent with each other. At least in some cases, such as p53 (26) and the glucocorticoid receptor (27), the DNA wrapping in nucleosomes can facilitate the binding of a TF to its cognate sequence, provided that the latter is properly exposed in chromatin.
Victor B. Zhurkin
Laboratory of Cell Biology, NCI, NIH
Bethesda, MD 20892