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Ayed, Ayeda; Mulder, Frans A. A.; Yi, Gwan‐Su; Lu, Ying; Kay, Lewis E.; Arrowsmith, C.H.

doi:10.1038/nsb0901-756

Cited by 263 publications

(114 citation statements)

References 38 publications

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“…The first study showed that RSp53 binds readily to its sequence-specific DNA target without activation, but in the presence of a large excess of non-specific competitor DNA this binding requires activation (Nichols and Matthews, 2001). In the second study, a dimeric p53 protein with an intact C-terminus was also shown to bind to its DNA target in the absence of non-specific competitor DNA, although its binding affinity was lower than that of the C-terminus truncated protein (Ayed et al, 2001). In addition, the NMR spectra of the two dimeric proteins were indistinguishable, suggesting that the 'latent' and 'active' proteins adopt similar conformations in the absence of DNA (Ayed et al, 2001).…”

Section: Discussionmentioning

confidence: 89%

DNA binding and 3′–5′ exonuclease activity in the murine alternatively-spliced p53 protein

et al. 2002

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In this study we show that the naturally occurring Cterminally alternative spliced p53 (referred to as AS-p53) is active as a sequence-specific DNA binding protein as well as a 3' -5'-exonuclease in the presence of Mg 2+ ions. The two activities are positively correlated as the sequence-specific DNA target is more efficiently degraded than a non-specific target. In contrast, a mutated AS-p53 protein that is deficient in DNA binding lacks exonuclease activity. The use of modified p53 binding sites, where the 3'-phosphate is replaced by a phosphorothioate group, enabled the inhibition of DNA degradation under the binding conditions. We demonstrate that AS-p53 interacts with its specific DNA target by two distinct binding modes: a high-affinity mode characterized by a low-mobility protein-DNA complex at the nanomolar range, and a low-affinity mode shown by a high-mobility complex at the micromolar range. Comparison of the data on the natural and the modified p53 binding sites suggests that the high-affinity mode is related to AS-p53 function as a transcription factor and that the low-affinity mode is associated with its exonuclease activity. The implications of these findings to a specific cellular role of AS-p53 are discussed.

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Section: Discussionmentioning

confidence: 89%

DNA binding and 3′–5′ exonuclease activity in the murine alternatively-spliced p53 protein

et al. 2002

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“…Thus, p53 is not 'latent' for p53-SSDB per se, but it appears like being 'latent' with certain types of DNA templates. Further supporting the conclusion, comparative structural analyses revealed that the global conformation of the p53-DBD is largely uninfluenced by the p53-CTD, 13 a finding that undermined a stronghold of the 'p53 latency' concept postulating that p53-CTD inhibits p53-SSDB by conformationally inhibiting the p53-DBD. Finally, the decisive evidence eliciting the impact of the p53-CTD on p53-SSDB under physiological conditions was provided recently in a recent study by McKinney et al 5 demonstrating that deletion of the p53-CTD impairs p53-SSDB and the potential of p53 to activate transcription in vivo.…”

mentioning

confidence: 70%

“…Cell Death and Differentiation (2006) 13,[885][886][887][888][889] Initially, the long known ability of p53 to sense structurally distorted DNA was considered to underlie primarily the interaction of p53 with aberrant sites in damaged DNA that may occur anywhere in the genome and therefore cannot be sequence-dependent. The fact that in vitro, distinct domains of the p53 protein elicit different modes of DNA binding independently from each other seemed to further support the idea that the different modes of p53 DNA binding are functionally unrelated: whereas p53-SSDB is a major function of the p53 core DNA binding domain (p53-DBD), 8 p53 binding to aberrant DNA structures has been firmly associated with the p53 C-terminal domain (p53-CTD), which can bind efficiently different types of aberrant DNA sites in the absence of the p53-DBD.…”

mentioning

confidence: 99%

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

Kim

Deppert

2006

Cell Death Differ

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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...

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“…Positive regulation of SSDB by the C-terminus was observed by Gohler et al (2002) in studies of p53 binding to stem loop oligo structures, and by McKinney and Prives (2002), who studied p53 binding to the 66 bp oligo (containing a p53 binding site) when it was locked in a microcircle. The question of the mechanism of p53 latency and the role of the C-terminus has been intensively discussed (Ayed et al, 2001;Yakovleva et al (2001) and references therein). This discussion may soon lead to more complex models involving not only the interactions and conformations of p53, but also the global and local DNA structures, as well as the positive regulation of p53 binding.…”

Section: Effect Of Supercoiling On P53 Dna Sequence-specific Bindingmentioning

confidence: 99%

Enhancement of p53 sequence-specific binding by DNA supercoiling

et al. 2004

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Using a new competition assay, we investigated the effect of DNA negative supercoiling on the DNA sequencespecific binding (SSDB) of human wild-type (wt) p53 protein. We found that supercoiled (sc) pBluescript DNAs with different inserted p53 target sequences were stronger competitors than a mixture of scDNA pBluescript with the given 20-mer target oligodeoxynucleotide. ScDNAs were always better competitors than their linearized or relaxed forms. Two DNAs with extruded cruciforms within the target sequence were the best competitors; removal of the cruciforms resulted in a decrease of competitor strength. In contrast to the full-length wt p53, the deletion mutant p53CD30 and the p53 core domain (93-312 aa) showed no enhancement of p53 SSDB to scDNA, suggesting that, in addition to the p53 core domain, the C-terminal was involved in this binding. We conclude that cruciforms and DNA bends contribute to the enhancement of p53 SSDB to scDNA and that the DNA supercoiling is an important determinant in the p53 sequence-specific binding. Supercoiling may thus play a significant role in the complex p53-regulatory network.

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Untitled

Cited by 263 publications

References 38 publications

DNA binding and 3′–5′ exonuclease activity in the murine alternatively-spliced p53 protein

DNA binding and 3′–5′ exonuclease activity in the murine alternatively-spliced p53 protein

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

Enhancement of p53 sequence-specific binding by DNA supercoiling

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