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

Simon S. McDade, Daksha Patel, Michael Moran, James Campbell, Kerry Fenwick, Iwanka Kozarewa, Nicholas J. Orr, Christopher J. Lord, Alan A. Ashworth, Dennis J. McCance

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)6270-6285
Number of pages16
JournalNucleic Acids Research
Volume42
Issue number10
Early online date13 May 2014
DOIs
Publication statusPublished - 02 Jun 2014

Bibliographical note

© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Keywords

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

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    McDade, S. S., Patel, D., Moran, M., Campbell, J., Fenwick, K., Kozarewa, I., Orr, N. J., Lord, C. J., Ashworth, A. A., & McCance, D. J. (2014). Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress. Nucleic Acids Research, 42(10), 6270-6285. https://doi.org/10.1093/nar/gku299