Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Yi, Jae-Seon; Cherny, Dmitry; Heim, Gudrun; Jovin, Thomas M.; Schäffer, Tilman E.

doi:10.1006/jmbi.2001.5129

Cited by 81 publications

(65 citation statements)

References 46 publications

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“…Atomic-force microscopy has shown two modes of p53-DNA recognition, (i) direct binding, and (ii) an initial nonspecific binding with subsequent sliding to the specific site (35). A large protein-DNA interface interferes with the sliding (34).…”

Section: A-b Dimer or B-c Dimer: Comparison With Experimental Resultsmentioning

confidence: 99%

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Pan

Gunasekaran

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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p53, the tumor suppressor protein, functions as a dimer of dimers. However, how the tetramer binds to the DNA is still an open question. In the crystal structure, three copies of the p53 monomers (containing chains A, B, and C) were crystallized with the DNAconsensus element. Although the structure provides crucial data on the p53-DNA contacts, the active oligomeric state is unclear because the two dimeric (A-B and B-C) interfaces present in the crystal cannot both exist in the tetramer. Here, we address the question of which of these two dimeric interfaces may be more biologically relevant. We analyze the sequence and structural properties of the p53-p53 dimeric interfaces and carry out extensive molecular dynamics simulations of the crystal structures of the human and mouse p53 dimers. We find that the A-B interface residues are more conserved than those of the B-C. Molecular dynamics simulations show that the A-B interface can provide a stable DNA-binding motif in the dimeric state, unlike B-C. Our results indicate that the interface between chains A-B in the p53-DNA complex constitutes a better candidate for a stable biological interface, whereas the B-C interface is more likely to be due to crystal packing. Thus, they have significant implications toward our understanding of DNA binding by p53 as well as p53-mediated interactions with other proteins. p53 dimeric interface ͉ p53 tetramer ͉ hot spots ͉ cancer ͉ gene regulation

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Section: A-b Dimer or B-c Dimer: Comparison With Experimental Resultsmentioning

confidence: 99%

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Pan

Gunasekaran

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…This is due to the fact that p53 proteins bound on distal and proximal clusters of p53REs interact and form a DNA loop, maximizing the integration and translocation of stress signals to p53-responsive promoters. [99][100][101] Hence, we speculate that p53-inducible proapoptotic genes would contain clusters of p53RE with low affinity for p53, p63, and p73 isoforms so that a maximum of stress signals has to be integrated and translocated to promoters by the p53 protein family to induce the expression of deadly proapoptotic genes. Reciprocally, one would predict that promoters of genes involved in cell cycle arrest contain p53RE with high affinity for a wide range of p53, p63, and p73 isoforms so that they are the first induced in response to a vast diversity of stress signals.…”

Section: Monographsmentioning

confidence: 99%

p53 Isoforms: An Intracellular Microprocessor?

Khoury¹,

Bourdon²

2011

Genes & Cancer

146

125

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Normal function of the p53 pathway is ubiquitously lost in cancers either through mutation or inactivating interaction with viral or cellular proteins. However, it is difficult in clinical studies to link p53 mutation status to cancer treatment and clinical outcome, suggesting that the p53 pathway is not fully understood. We have recently reported that the human p53 gene expresses not only 1 but 12 different p53 proteins (isoforms) due to alternative splicing, alternative initiation of translation, and alternative promoter usage. p53 isoform proteins thus contain distinct protein domains. They are expressed in normal human tissues but are abnormally expressed in a wide range of cancer types. We have recently reported that p53 isoform expression is associated with breast cancer prognosis, suggesting that they play a role in carcinogenesis. Indeed, the cellular response to damages can be switched from cell cycle arrest to apoptosis by only manipulating p53 isoform expression. This may provide an explanation to the hitherto inconsistent relationship between p53 mutation, treatment response, and outcome in breast cancer. However, the molecular mechanism is still unknown. Recent reports suggest that it involves modulation of gene expression in a p53-dependent and -independent manner. In this review, we summarize our current knowledge about the biological activities of p53 isoforms and propose a molecular mechanism conciliating our current knowledge on p53 and integrating p63 and p73 isoforms in the p53 pathway.

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“…Local changes in rigidity, curvature and/or topology of a DNA molecule induced by chemical compounds or by DNA binding proteins [7,8,9,10,11,12] have been also studied. However, the three dimensional conformation of a flexible biopolymer is not directly delivered by the AFM, but we show here that such information can be extracted from the AFM images.…”

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confidence: 99%

Scaling Exponents and Probability Distributions of DNA End-to-End Distance

et al. 2005

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Correlation length exponent ν for long linear DNA molecules was determined by direct measurement of the average end-to-end distance as a function of the contour length s by means of atomic force microscopy (AFM). Linear DNA, up to 48'502 base pairs (bp), was irreversibly deposited from a solution onto silanized mica and imaged in air. Under the adsorption conditions used, the DNA is trapped onto the surface without any two-dimensional equilibration. The measured exponent is ν = 0.589 ± 0.006, in agreement with the theoretical 3D value of ν = 0.5880 ± 0.0010.The persistence length ℓ p of DNA was estimated to be 44±3 nm, in agreement with the literature values. The distribution of the end-to-end distances for a given contour length s and the exponents characterizing the distribution were determined for different s. For s smaller or comparable to ℓ p , a delta function like distribution was observed, while for larger s, a probability distribution of the type x d−1 x g e −bx δ was observed with g = 0.33±0.22 and δ = 2.58±0.76. These values are compared to the theoretical exponents for Self-Avoiding Walk (SAW): namely g = γ−1 ν and δ = (1 − ν) −1 . So for d = 2, g ≈ 0.44 and δ = 4, while for d = 3, g ≈ 0.33 and δ ≈ 2.5. The derived entropic exponent γ is γ = 1.194 ± 0.129. The present data indicate that the DNA behaves on large length scales like a 3 dimensional SAW.

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Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Cited by 81 publications

References 46 publications

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

Comparison of the protein–protein interfaces in the p53–DNA crystal structures: Towards elucidation of the biological interface

p53 Isoforms: An Intracellular Microprocessor?

Scaling Exponents and Probability Distributions of DNA End-to-End Distance

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