Book of Abstracts: Albany 2007
June 19-23 2007
Specific recognition of DNA by p53 and its dependence on DNA structural properties
The DNA binding activity of p53 is pivotal to its tumor suppressor activity. The core domain of p53 interacts directly with defined DNA sequences and is the main target for mutations in human primary tumors. These binding interactions initiate a cascade of events leading to (but are not limited to) growth arrest and apoptosis. Numerous putative p53 binding sites have been identified by genome-wide analyses, and by various bioinformatics approaches. In vitro and in vivo studies have revealed that p53 binding as well as transcriptional activation from adjacent genes vary by more than three order of magnitude depending on the identity of the p53 DNA binding sites, its internal arrangement, the number of such elements, and their location with respect to the transcription start site. The DNA target sites of p53 are highly variable. The consensus binding site consists of two decameric repeats with the general form RRRCWWGYYY (R=A,G;W=A,T;Y=C,T), separated by 0-13 base pairs. The full-length consensus sequence contains two half-sites, which can also be viewed as four pentameric quarter sites, oriented in alternating directions. The high degeneracy of the consensus-binding site must entail that specificity and selectivity are conferred to p53/DNA interactions by means other than direct sequence recognition. We will present our studies on the interaction of p53 DNA binding domain with consensus-like binding sites, as a function of base pairs known to be involved in either direct or indirect readout of the DNA, the spacer region between two half sites, the relative orientations of two half-sites, as well as the number of half sites.
Tali E. Haran
Dept of Biology