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p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions
1Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc. NCI-Frederick, Frederick, Maryland 21702, USA.
Abstract:
Specific p53 binding-induced DNA bending and its underlying responsible forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome; however, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half-site, different DNA bending extents were observed. The analysis showed that the dimer-dimer interactions in p53 were similar for the complexes; on the other hand, the specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120, and Arg248 with the DNA, varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory, whereas those for the CTAG sequence were partially dissociated in part of the trajectory, which affected the stability of the nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which is in turn related to the DNA sequence and DNA flexibility.
Insights
DNA bending by p53 is sequence-dependent. Molecular dynamics simulations reveal that specific DNA sequences, like CATG, stabilize p53-DNA interactions, influencing transcription factor binding and gene activation.
Area of Science:
- Molecular Biology
- Biophysics
- Genetics
Background:
- Specific p53 binding to DNA induces bending, a critical process for selective transcription activation.
- The genomic p53-response elements vary, but the determinants and extent of DNA bending remain unclear.
Purpose of the Study:
- To investigate the forces governing DNA bending induced by p53 binding.
- To understand how DNA sequence variations influence p53-DNA complex stability and bending.
Main Methods:
- Molecular dynamics simulations were conducted on p53 core domain tetramer-DNA complexes.
- The central 4-base pair sequences of DNA half-sites were systematically varied.
- Analysis focused on p53 dimer-dimer and p53-DNA interactions, including specific amino acid contacts.
Main Results:
- DNA bending extent varied with DNA sequence, particularly in the central 4 base pairs.
- p53 dimer-dimer interactions remained consistent, while p53-DNA interactions, especially involving Arg280, showed sequence-dependent variations.
- The CATG sequence maintained stable base pairings and Arg280-DNA interactions, unlike the CTAG sequence.
Conclusions:
- DNA bending by p53 is a result of the interplay between p53 self-interaction and p53-DNA binding.
- DNA sequence and inherent flexibility critically modulate these interactions, affecting transcription factor binding and gene regulation.
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