p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions

Yongping Pan1, Ruth Nussinov

  • 1Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc. NCI-Frederick, Frederick, Maryland 21702, USA.

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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