TY  - JOUR
A1  - Schlereth, Katharina
A1  - Heyl, Charlotte
A1  - Krampitz, Anna-Maria
A1  - Mernberger, Marco
A1  - Finkernagel, Florian
A1  - Scharfe, Maren
A1  - Jarek, Michael
A1  - Leich, Ellen
A1  - Rosenwald, Andreas
A1  - Stiewe, Thorsten
T1  - Characterization of the p53 Cistrome - DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions
JF  - PLOS Genetics
N2  - 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.
KW  - cell-cycle arrest
KW  - gene expression
KW  - breast cancer
KW  - human genome
KW  - transcriptional repression
KW  - consensus DNA
KW  - in-vivo
KW  - apoptosis
KW  - network
KW  - damage
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127579
SN  - 1553-7404
VL  - 9
IS  - 8
ER  - 
TY  - JOUR
A1  - Timofeev, Oleg
A1  - Schlereth, Katharina
A1  - Wanzel, Michael
A1  - Braun, Attila
A1  - Nieswandt, Bernhard
A1  - Pagenstecher, Axel
A1  - Rosenwald, Andreas
A1  - Elsässer, Hans-Peter
A1  - Stiewe, Thorsten
T1  - p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo
JF  - Cell Reports
N2  - Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer.
KW  - mutant p53
KW  - senescence
KW  - mice
KW  - tumorigenesis
KW  - restoration
KW  - damage responses
KW  - antioxidant function
KW  - p53-inducible regulator
KW  - p53-dependent apoptosis
KW  - cell-cycle arrest
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122168
VL  - 3
ER  -