Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277

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Jiri Buzek1, Leena Latonen, Sari Kurki

  • 1Department of Virology, Haartman Institute, and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital Laboratory Diagnostics, PO Box 63, FIN-00014 Helsinki, Finland.

Nucleic Acids Research
|May 30, 2002
PubMed

Insights

DNA damage induces p53 accumulation, altering its binding to specific DNA elements. This study reveals a novel mechanism of differential p53 binding affinity to distinct responsive elements, crucial for gene regulation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • The tumor suppressor protein p53 plays a critical role in cellular responses to DNA damage.
  • p53 regulates the expression of numerous genes involved in cell cycle arrest, apoptosis, and DNA repair.
  • The binding of p53 to specific DNA sequences, known as p53-responsive elements (REs), is essential for its transcriptional activity.

Purpose of the Study:

  • To investigate the binding capacity of DNA damage-induced p53 to various p53-REs in human diploid fibroblasts.
  • To elucidate the mechanism underlying differential p53 binding affinity to distinct REs.

Main Methods:

  • Bio-oligo pull-down DNA-binding assay.
  • Analysis of p53 binding to GADD45 and p21(WAF1/CIP1) REs during p53 accumulation.
  • Site-directed mutagenesis of GADD45 RE sequences and p53 Cys277.

Main Results:

  • p53 binding affinity decreased for the GADD45 RE but remained unchanged for the p21(WAF1/CIP1) RE during p53 accumulation.
  • Differential binding to the GADD45 RE was dependent on cytosines at position 3 of RE pentamers and the p53 redox state.
  • Cys277 in p53 was identified as critical for the differential regulation of GADD45 in DNA-damaged cells.

Conclusions:

  • A novel mechanism for differential p53 binding affinity to distinct REs was uncovered.
  • The redox state of p53 and specific DNA sequence features modulate p53's transcriptional regulation in response to DNA damage.

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