iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

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Updated: Jan 21, 2026

DNA Sequence Recognition by DNA Primase Using High-Throughput Primase Profiling
08:04

DNA Sequence Recognition by DNA Primase Using High-Throughput Primase Profiling

Published on: October 8, 2019

9.1K

Shuo Chen1, Jiale Wu2, Shan Zhong1

  • 1Ludwig Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|August 10, 2019
PubMed

Insights

The tumor suppressor p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Structural Biology

Background:

  • The p53 protein is a crucial transcription factor frequently mutated in human cancers.
  • p53's regulation of genes controlling cell fate is essential but not fully understood.
  • Context-dependent modulation of p53 activity is critical for cellular balance.

Purpose of the Study:

  • To investigate how the cofactor iASPP modulates p53's interaction with DNA.
  • To elucidate the structural basis of p53-iASPP interaction.
  • To identify new strategies for p53-targeting cancer therapies.

Main Methods:

  • Identification of sequence signatures in p53-binding sites affected by iASPP.
  • X-ray crystallography to determine the structure of the p53-iASPP complex.
  • Structural analysis of protein-DNA interactions.

Main Results:

  • iASPP binds to a distinct surface on p53, displacing the L1 loop.
  • This interaction fine-tunes p53's sequence-specific DNA binding without altering other DNA-recognition modules.
  • The iASPP binding site differs from those of other known p53-interacting proteins, except for HPV E6.

Conclusions:

  • iASPP inhibits p53 function through a unique mechanism involving the L1 loop.
  • This distinct interaction site offers a novel target for developing precision cancer medicines.
  • Targeting the p53-iASPP interaction may lead to improved cancer therapeutics.
Keywords:
HPV E6crystal structureiASPPp53target selectivity

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