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The Rich World of p53 DNA Binding Targets: The Role of DNA Structure - PubMed

  • ️Tue Jan 01 2019

Review

The Rich World of p53 DNA Binding Targets: The Role of DNA Structure

Václav Brázda et al. Int J Mol Sci. 2019.

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.

Keywords: consensus sequence; cruciform; local DNA structures; p53; protein-DNA interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Various double-stranded DNA conformations, right-handed: A-DNA, B-DNA, C-DNA, left-handed: Z-DNA (from left to right). First row–upper view, second row–side view. A-DNA–AGGGGCCCCT repeat, B-DNA–random sequence, Z-DNA–CG repeat. Visualized using Chimera software, A–blue, C–yellow, G–green, T–red.

Figure 2
Figure 2

In silico model of human p53 interactions with Z-DNA (A), Triplex DNA (B) and G-quadruplex DNA (C). Visualized using Chimera software, Protein: helices-red, beta-sheets-green, DNA: A–blue, C–yellow, G–green, T–red.

Figure 3
Figure 3

DNA structures with various numbers of strands (A) hemicatenate DNA (single- and four-stranded parts), (B) T-loop (single-, four-stranded part with DNA junction) (C) Triplex DNA (single- and three-stranded DNA), (D) G-quadruplex (four-stranded) (E) I-motif (four-stranded) (F) Cruciform with loops (single-, double- and four-stranded junction). Parts B, C, D, and F are adapted from [83].

Figure 4
Figure 4

Cruciform structure formation (A) inverted repeat (red) without spacer (left part) or with spacer (green–right part) is required for (B) cruciform structure formation, the length of the repeat and spacer influence the length of the single-stranded loop (a), size of the stem (b). Every cruciform consist of four-way junction (c). Two p53 half-sites formed by inverted repeats could be close in cruciform structure allowing effective binding of p53 (blue) (C).

Figure 5
Figure 5

Frequencies and localization of inverted repeats in p53-ChIPed fragments, within a p53 double-stranded target, 20-bp around and 100-bp around.

Figure 6
Figure 6

Various targets for wild-type (A-blue) and mutant (B-violet) proteins.

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