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. 2009 Jul;5(7):e1000448.
doi: 10.1371/journal.pcbi.1000448. Epub 2009 Jul 24.

Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view

Yongping Pan  1 , Ruth Nussinov
Affiliations

Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view

Yongping Pan et al. PLoS Comput Biol. 2009 Jul.

Abstract

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0-2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Structural changes of three Shakked's crystal structure-based p53 core domain-DNA complexes during the 60-ns molecular dynamics simulations.
(A) Cα-RMSD of the p53 tetramer for the crystal structure (‘Xtal’) and of the crystal structure with DNA linked (‘Link’). (B) p53 core domain dimer-dimer interaction energy changes in the simulations for the crystal structure and the crystal structure with the DNA linked. (C) Comparison of the conformations of the starting crystal structure, snapshot at 50 ns from the simulations of the crystal structure and the crystal structure with the DNA segments linked.
Figure 2
Figure 2. p53 dimer-dimer interaction energies for various dimer-dimer organizations derived by rotating one p53 dimer with respect to the other in the tetrameric p53-DNA complex.
(A) Illustration of the relationship between the rotation angle and the change of the p53 dimer-dimer organization. The rotation angle was defined as 0 when the two dimers were aligned. Clockwise rotation of the p53 dimer at the front (red and cyan) resulted in a positive angle and a negative angle otherwise. (B) The p53 dimer-dimer interaction energy changes upon the changes of the dimer-dimer organization. Rotation angles beyond the range shown in the plot were not presented due to unrealistic twisting of the DNA. The most favorable organization based on the dimer-dimer interaction energy was the one with a rotation angle near 0.
Figure 3
Figure 3. Structural and energy properties of the four complexes with spacer sizes of 1, 2, 9 and 10 base pairs.
(A) and (B) p53 dimer-dimer interaction energy and p53-DNA interaction energy, respectively. (C) and (D) the distance between the centers mass for the two pairs of p53 core domain for one and ten bp insertion complexes, respectively. The interacting p53 core domain pairs were labeled in Figure 4.
Figure 4
Figure 4. p53 core domain tetramer-DNA complex model with 1-bp insertion.
(A) Starting structure conformation with four p53 subunits labeled a1, b1, a2 and b2, respectively and (B) average structure of the last 5 ns trajectory (55–60 ns) with two views for each structure. The motifs involved in the interactions at the interface including loop L2 (shown in magenta) from one subunit and those residues between strand S5 and α-helix 1 (colored cyan) in the other were highlighted. (C) Atomic details of the interactions at the dimer-dimer interface. The backbone of the core domains were colored same as in (B). Residues that are within 7 angstroms of the other domains were shown in thin sticks. Interacting residues were related with dotted lines.
Figure 5
Figure 5. p53 core domain tetramer-DNA complex model with 10-bp insertion.
(A) Starting structure conformation. (B) Final structure after the simulation (60 ns). Residues within 4.5 angstroms across the interface in the starting conformations are shown in sticks. In the final conformation, the monomer pair of the dimer interface lost their interactions. p53 subunits were labeled a1, b1, a2, and b2, respectively.
Figure 6
Figure 6. Comparison of the DNA structures from different simulations.
(A) Average structure (55–60 ns) from the trajectory of Shakked's crystal structure with the DNA linked. (B) Average structure (55–60 ns) from the one base pair insertion complex simulation. (C) Superposition of (A) and (B). The positions for the two base pairs that were highlighted in cyan and blue were labeled. The superposition shows that the two bases (3 and 22) in the crystal structure overlapped well with the two bases (3 and 21) in the one base pair insertion complex. This figure shows the DNA unwinding and compression in conformation derived from the crystal structure simulation.
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References

    1. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991;51:6304–6311. - PubMed
    1. el-Deiry WS. Regulation of p53 downstream genes. Semin Cancer Biol. 1998;8:345–357. - PubMed
    1. Vousden KH. Activation of the p53 tumor suppressor protein. Biochim Biophys Acta. 2002;1602:47–59. - PubMed
    1. Balagurumoorthy P, Sakamoto H, Lewis MS, Zambrano N, Clore GM, et al. Four p53 DNA-binding domain peptides bind natural p53-response elements and bend the DNA. Proc Natl Acad Sci U S A. 1995;92:8591–8595. - PMC - PubMed
    1. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992;1:45–49. - PubMed

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