The tumor suppressor p53, a classical transcription factor, is activated by diverse signals associated with various cellular and genotoxic stress responses and, through its selective activation of cognate target genes, induces either cell cycle arrest (allowing DNA repair) or apoptosis. The broad objective is to understand the underlying mechanisms and, ultimately, the basis for differential activation of p53 target genes and cell fate decisions that result in repair or elimination of potentially malignant cells with damaged DNA. Recent studies indicate that the function of p53 is mediated by a number of transcriptional co-activators that act either by effecting modifications (acetylation, methylation, phosphorylation, ubiquitination) of nucleosomal histones or p53 itself (e.g. pSOO/CBP, GCN5, TIP60, PRMT1, CARM1, MLL1), or by facilitating direct communication with the basal transcriptional machinery (e.g. Mediator), or by unknown mechanisms (e.g. ASPP, JMY, p63, p73). In particular, cellular assays and biochemical assays reconstituted with purified factors and either DNA or recombinant chromatin templates have established both independent and ordered cooperative functions of histone acetyltransferases and methyltransferases, DNA damage-induced interactions of cofactors with p53, and DNA damage-induced association of multiple coactivators on a single p53 target gene. In a major extension of this work, using both in vitro and in vivo assays, the specific aims are (i) to employ defined cell free systems, with purified factors and DNA templates, to detail the function and mechanism of action of p53 co-activators that facilitate direct (post chromatin remodeling) activation of the general transcription machinery, (ii) to establish defined cell free systems, with purified factors and recombinant chromatin templates, to investigate the function and mechanism of action of p53 co-activators that effect covalent histone modifications and chromatin remodeling, (iii) to investigate the role of DNA damage-induced covalent modifications of p53 in the function of cofactors that directly (Mediator) or indirectly (chromatin modifying factors) effect target gene activation, (iv) to employ cell-based assays (ChIP, RNA interference, gene knockout/knockin) to establish the in vivo accumulation and function of co-activators on p53 target genes in response to DNA damage, and (v) to assess variations in cofactor usage as a function of different genotoxic agents, different cell types, and different p53 target genes (apoptotic versus cell cycle arrest), as well as a possible co-activator redundancy that may contribute to biological robustness for any given DNA damage response. Cancer represents a major health problem and over half of human cancers have defects in p53 or ,in some cases, factors that regulate p53, resulting in abnormal growth of cells with damaged DNA and, ultimately, the emergence of malignant cells. Understanding the mechanisms by which p53 target genes are controlled may facilitate development of ways to counter the adverse effects of altered p53 function.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Genetics B Study Section (MGB)
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Mietz, Judy
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Rockefeller University
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New York
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