The versatile interactions of p53 with DNA: when flexibility serves specificity

Abstract

The tumor suppressor p53 exerts versatile interactions with DNA. Of importance is the binding of wild-type p53 to p53-responsive elements in promoters of p53 target genes. This interaction is complex and determined by DNA sequence and structure, and involves the p53 core DNA binding and the C-terminal domain. In addition, wild-type p53 binds linear DNA with high affinity in a sequence-independent manner, and non-B DNA in a DNA strictly structure-selective mode that is not dependent on the presence of a p53-responsive element. Mutant p53 has lost sequence-specific DNA binding and high-affinity binding to linear DNA, but has retained the ability to interact with DNA in a structure-selective manner. We discuss the interactions of p53 with DNA, which are characterized by a high flexibility, both on the side of p53 and DNA, thereby providing p53 with the specificity required for its functions.The major molecular property of p53 is that of a DNA binding protein. Consequently, its interaction with DNA is central to various p53-mediated activities. Best known and analyzed is the sequence-specific DNA binding of p53 (p53-SSDB), followed by transcriptional activation of genes involved in regulation of the cell cycle, DNA repair or apoptosis, upon activation of the p53 pathway by endogenous or exogenous stress factors. 1 Another p53 stress response is the binding of p53 to damaged sites in DNA, considered to serve as a platform for recruiting repair factors to the sites of the lesions (reviewed by Sengupta and Harris 2 ). However, also in non-stressed cells, some p53 activities involved in the 'routine' maintenance of genomic integrity rely on p53 interactions with genomic DNA, particularly at sites of active metabolic processes that render DNA vulnerable or prone to potential structural re-arrangements. In this respect, it has been shown that p53 binds to recombination intermediates, Holliday junctions (reviewed by Sengupta and Harris 2 ) or telomeric t-loops. 3 Reflecting the diversity of p53 functions that involve its interaction with DNA, p53 binds to DNA in very different modes that differ for the type of target DNA and in their modes of DNA recognition. Recognition and binding affinity of the various p53 DNA interactions are determined either by the presence of specific sequence motifs (sequencespecific DNA binding, p53-SSDB) or by specific structural determinants presented by DNA in non-B DNA conformations (DNA structure-selective binding, p53-DSSB). Regardless of whether the p53 target site is determined by the presence of a specific sequence motif or by the three-dimensional structure of the DNA, either mode of DNA recognition ensures the specificity of the interaction. Last but not least, in addition to the different modes of recognition that underlie the sitespecific targeting of p53 to DNA, as in p53-SSDB or p53-DSSB, high-affinity binding of wild-type p53 to unspecific linear double-stranded DNA represents yet another mode of interaction that probably is important for targeting p53 to its specific response ele...

Mutant p53: an oncogenic transcription factor

“…Despite rapidly accumulating evidence, the knowledge of the molecular details of the transcriptional activity of mutant p53 is still very scarce; (c) recent work by Di Agostino et al Mutant p53: an oncogenic transcription factor S Strano et al mutant p53 is recruited in vivo to such regulatory regions through the physical interaction with the transcription factor NF-Y (Figure 3). Altogether, these results show that the repertoire of the genes regulated by p53 gain-offunction mutants can be dictated by the specific interaction partner; (d) original work from Deppert's lab has shown that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity with nuclear matrix attachment region DNA in vitro Koga and Deppert, 2000;Gohler et al, 2005;Kim and Deppert, 2006). These findings suggest that mutant p53 interacting with key structural components of the nucleus exerts its gain-of-function activity through the perturbation of the nuclear structure and function.…”

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

“…We also considered the possibility that p53 binds directly in a sequence independent manner to repetitive or low complexity sequences that might serve as a structural binding motif. 11 However, this is unlikely because only 6.9% of the peaks with no motif were in repeats (UCSC repeat masker) compared with 28% of the 743 peaks found in repeats.…”

“…10 It also can bind to simple repeats and a variety of DNA structures and mismatches, although these have not been shown to affect transcription. 11,12 Binding of p53 to DNA is highly cooperative, 13 which has been proposed to be particularly important at imperfect binding sites. 14 Despite the fact that 20% of the putative p53 binding sites contain one or more CpG dinucleotides, and p53 binding was proposed to be affected by their methylation state, 15 the impact of DNA methylation on p53 genome-wide binding has not been investigated in vivo.…”

Outcomes of p53 activation - spoilt for choice

“…However, additional complexity is provided by evidence that modulation of p53 itself may also allow the differential recognition of target-gene promoters. One interesting possibility is that changes in the conformation of p53 allow selective recognition of different p53-binding sites, a suggestion that is supported by the high degree of flexibility seen in the ability of p53 to bind DNA (Kim and Deppert, 2006). This model might mean that the mutants of p53 that only activate expression of one group of genes are locked in the conformation that only recognises the binding sites present in these promoters.…”