Abstract
The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain so-called p53 response elements in their promoters, consisting of 20 bp long canonical consensus sequences. Compared to other transcription factors, which usually bind to one concrete and clearly defined DNA target, the p53 consensus sequence is not strict, but contains two repeats of a 5′RRRCWWGYYY3′ sequence; therefore it varies remarkably among target genes. Moreover, p53 binds also to DNA fragments that at least partially and often completely lack this consensus sequence. p53 also binds with high affinity to a variety of non-B DNA structures including Holliday junctions, cruciform structures, quadruplex DNA, triplex DNA, DNA loops, bulged DNA, and hemicatenane DNA. In this review, we summarize information of the interactions of p53 with various DNA targets and discuss the functional consequences of the rich world of p53 DNA binding targets for its complex regulatory functions.
Highlights
The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes
Compared to many other transcription factors, p53 DNA targets are not defined by a particular consensus sequence, but p53 is able to bind various DNA sequences and DNA targets defined by their secondary structures
Complete mutagenesis of the p53 DNA target, which is typically formed by two copies of a 5 -RRRCWWGYYY-3 sequence, provides information concerning p53 binding affinities for all possible consensus p53 targets and it is easy to compute the theoretical p53 binding affinity to the target in its linear B-DNA form [56,57]. p53 is able to search for its target by sliding [29,58,59] and can promote intersegmental transfer by binding to two DNA strands simultaneously [60]
Summary
P53 is the most often mutated tumor suppressor in humans and is studied intensively from different points of view due to its crucial role in malignant transformation [1,2,3]. p53 functions include regulatory roles in processes such as ontogenesis [4,5,6], myogenesis [7], metabolism [8], cell cycle arrest [9,10], apoptosis [11,12], angiogenesis [13,14], DNA repair [15,16], and cell senescence [16,17]. Compared to many other transcription factors, p53 DNA targets are not defined by a particular consensus sequence, but p53 is able to bind various DNA sequences and DNA targets defined by their secondary structures Many of these local DNA structures are conserved throughout evolution and play essential roles in regulating many biological processes [30,31,32]. Bioinformatic analyses demonstrated non-random locations within the genome for certain local DNA structures, for example origins of replication (cruciforms), promoter regions (cruciforms, triplexes, and G-quadruplexes), introns (triplexes) and telomeres (G-quadruplexes) [35,36,37,38,39,40,41] In keeping with their important regulatory roles, many local DNA structures are important in human diseases, for example triplex structure in the frataxin gene caused by GAA/TTC triplet expansion is associated with Friedreich’s ataxia [42,43]. We summarize published data about these interesting p53 DNA binding properties and hypothesize their possible roles
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