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

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Publication Date
2014-06
ICR Author
Lord, Christopher
Orr, Nicholas
Campbell, James
Author
McDade, SS
Patel, D
Moran, M
Campbell, J
Fenwick, K
Kozarewa, I
Orr, NJ
Lord, CJ
Ashworth, AA
McCance, DJ
Type
Journal Article
Metadata
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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.
URL
https://repository.icr.ac.uk/handle/internal/111
Collections
  • Breast Cancer Research
  • Molecular Pathology
Licenseref URL
https://creativecommons.org/licenses/by/4.0
Version of record
10.1093/nar/gku299
Subject
Cells, Cultured
Keratinocytes
Humans
Cisplatin
Doxorubicin
Tumor Suppressor Proteins
Transcription Factors
Mutagens
DNA Repair
Transcription, Genetic
Binding Sites
Genome, Human
Tumor Suppressor Protein p53
DNA Breaks, Double-Stranded
Stress, Physiological
Research team
Complex Trait Genetics
Gene Function
Language
eng
License start date
2014-06
Citation
Nucleic acids research, 2014, 42 (10), pp. 6270 - 6285

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