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Characterization of the p53 Cistrome - DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions

Please always quote using this URN: urn:nbn:de:bvb:20-opus-127579
  • p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context-and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensivelyp53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context-and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.show moreshow less

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Metadaten
Author: Katharina Schlereth, Charlotte Heyl, Anna-Maria Krampitz, Marco Mernberger, Florian Finkernagel, Maren Scharfe, Michael Jarek, Ellen Leich, Andreas Rosenwald, Thorsten Stiewe
URN:urn:nbn:de:bvb:20-opus-127579
Document Type:Journal article
Faculties:Medizinische Fakultät / Pathologisches Institut
Language:English
Parent Title (English):PLOS Genetics
ISSN:1553-7404
Year of Completion:2013
Volume:9
Issue:8
Pagenumber:e1003726
Source:PLoS Genetics 9(8): e1003726. doi:10.1371/journal.pgen.1003726
DOI:https://doi.org/10.1371/journal.pgen.1003726
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 611 Menschliche Anatomie, Zytologie, Histologie
Tag:apoptosis; breast cancer; cell-cycle arrest; consensus DNA; damage; gene expression; human genome; in-vivo; network; transcriptional repression
Release Date:2016/03/22
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung