Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.

2.50
Hdl Handle:
http://hdl.handle.net/10033/305876
Title:
Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.
Authors:
Schlereth, Katharina; Heyl, Charlotte; Krampitz, Anna-Maria; Mernberger, Marco; Finkernagel, Florian; Scharfe, Maren; Jarek, Michael; Leich, Ellen; Rosenwald, Andreas; Stiewe, Thorsten
Abstract:
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 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.
Affiliation:
Molecular Oncology, Philipps-University, Marburg, Germany.
Citation:
Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. 2013, 9 (8):e1003726 PLoS Genet.
Journal:
PLoS genetics
Issue Date:
Aug-2013
URI:
http://hdl.handle.net/10033/305876
DOI:
10.1371/journal.pgen.1003726
PubMed ID:
23966881
Type:
Article
Language:
en
ISSN:
1553-7404
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorSchlereth, Katharinaen
dc.contributor.authorHeyl, Charlotteen
dc.contributor.authorKrampitz, Anna-Mariaen
dc.contributor.authorMernberger, Marcoen
dc.contributor.authorFinkernagel, Florianen
dc.contributor.authorScharfe, Marenen
dc.contributor.authorJarek, Michaelen
dc.contributor.authorLeich, Ellenen
dc.contributor.authorRosenwald, Andreasen
dc.contributor.authorStiewe, Thorstenen
dc.date.accessioned2013-11-28T10:27:54Z-
dc.date.available2013-11-28T10:27:54Z-
dc.date.issued2013-08-
dc.identifier.citationCharacterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. 2013, 9 (8):e1003726 PLoS Genet.en
dc.identifier.issn1553-7404-
dc.identifier.pmid23966881-
dc.identifier.doi10.1371/journal.pgen.1003726-
dc.identifier.urihttp://hdl.handle.net/10033/305876-
dc.description.abstractp53 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.en
dc.language.isoenen
dc.rightsArchived with thanks to PLoS geneticsen
dc.titleCharacterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.en
dc.typeArticleen
dc.contributor.departmentMolecular Oncology, Philipps-University, Marburg, Germany.en
dc.identifier.journalPLoS geneticsen

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