Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress

Nucleic Acids Res. 2014 Jun;42(10):6270-85. doi: 10.1093/nar/gku299. Epub 2014 May 13.


In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome-wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53-dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveal that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Cisplatin / toxicity
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Doxorubicin / toxicity
  • Genome, Human
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Mutagens / toxicity*
  • Stress, Physiological / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism*


  • Mutagens
  • TP53 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Doxorubicin
  • Cisplatin

Associated data

  • GEO/GSE56640