dc.contributor.author | McDade, SS | |
dc.contributor.author | Patel, D | |
dc.contributor.author | Moran, M | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Fenwick, K | |
dc.contributor.author | Kozarewa, I | |
dc.contributor.author | Orr, NJ | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ashworth, AA | |
dc.contributor.author | McCance, DJ | |
dc.date.accessioned | 2016-09-14T09:56:19Z | |
dc.date.issued | 2014-01-01 | |
dc.identifier.citation | Nucleic acids research, 2014, 42 (10), pp. 6270 - 6285 | |
dc.identifier.issn | 0305-1048 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/111 | |
dc.identifier.eissn | 1362-4962 | |
dc.identifier.doi | 10.1093/nar/gku299 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 6270 - 6285 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | OXFORD UNIV PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cells, Cultured | |
dc.subject | Keratinocytes | |
dc.subject | Humans | |
dc.subject | Cisplatin | |
dc.subject | Doxorubicin | |
dc.subject | Tumor Suppressor Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Mutagens | |
dc.subject | DNA Repair | |
dc.subject | Transcription, Genetic | |
dc.subject | Binding Sites | |
dc.subject | Genome, Human | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.subject | DNA Breaks, Double-Stranded | |
dc.subject | Stress, Physiological | |
dc.title | Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1093/nar/gku299 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2014-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nucleic acids research | |
pubs.issue | 10 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Complex Trait Genetics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Complex Trait Genetics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 42 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Complex Trait Genetics | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Lord, Christopher | |