Dataset Information

Life or death: p53-induced apoptosis requires DNA binding cooperativity.

ABSTRACT: The tumor suppressor p53 provides exquisite protection from cancer by balancing cell survival and death in response to stress. Sustained stress or irreparable damage trigger p53's killer functions to permanently eliminate genetically-altered cells as a potential source of cancer. To prevent the unnecessary loss of cells that could cause premature aging as a result of stem cell attrition, the killer functions of p53 are tightly regulated and balanced against protector functions that promote damage repair and support survival in response to low stress or mild damage. In molecular terms these p53-based cell fate decisions involve protein interactions with cofactors and modifying enzymes, which modulate the activation of distinct sets of p53 target genes. In addition, we demonstrate that part of this regulation occurs at the level of DNA binding. We show that the killer function of p53 requires the four DNA binding domains within the p53 tetramer to interact with one another. These intermolecular interactions enable cooperative binding of p53 to less perfect response elements in the genome, which are present in many target genes essential for apoptosis. Modulating p53 interactions within the tetramer could therefore present a novel promising strategy to fine-tune p53-based cell fate decisions.

SUBMITTER: Schlereth K

PROVIDER: S-EPMC3055192 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Life or death: p53-induced apoptosis requires DNA binding cooperativity.

Schlereth Katharina K Charles Joël P JP Bretz Anne C AC Stiewe Thorsten T

Cell cycle (Georgetown, Tex.) 20101011 20

The tumor suppressor p53 provides exquisite protection from cancer by balancing cell survival and death in response to stress. Sustained stress or irreparable damage trigger p53's killer functions to permanently eliminate genetically-altered cells as a potential source of cancer. To prevent the unnecessary loss of cells that could cause premature aging as a result of stem cell attrition, the killer functions of p53 are tightly regulated and balanced against protector functions that promote damag ...[more]

PMID: 20948308

Similar Datasets

Project description: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.

Dataset Information

Life or death: p53-induced apoptosis requires DNA binding cooperativity.

Publications

Life or death: p53-induced apoptosis requires DNA binding cooperativity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets