Functional Mimicry of the p53 C-terminal Tail by the Ubiquitin-like Molecule SUMO

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DESCRIPTION (provided by applicant): The p53 tumor suppressor plays a key role in preventing tumorigenesis. p53 usually responds to various stress signals, and a major recognized trigger for activating p53 in cells is the presence of DNA damage or of DNA-replication stress due to the presence of oncogene products. Once activated, p53 can execute different programs, including senescence, apoptosis and cell cycle arrest. It is well recognized that post-translational modifications affect the ability of p53 to direct cells towards these different cellular programs, depending upon the nature of the signal. In this application we have studied the consequences of a-post-translational modifications of p53, sumoylation. SUMO is a ubiquitin-like molecule which is covalently attached to a variety of target substrates. By conducting these studies we have discovered that sumoylated p53 regulates the expression levels of an enzyme, acireductone dioxygenase, ARD/ADI1 that functions in the methionine salvage pathway. This is a key pathway that regulates the recycling of methionine. One important by-product of this pathway is S-adenosyl methionine (SAM), the major methyl donor for all trans-methylation reactions that involve DNA- and protein-methyltransferases. Interest in this metabolic pathway stems from several observations. First, the majority of cancer cell lines are methionine dependent, and there is evidence that alterations in the MTA pathway account for such dependency. Second, methylthioadenosine (MTA), a product of SAM metabolism, has important effects on DNA replication and cell cycle progression, which are altered in tumor cells. Third, the tumor-predisposing effects of alcoholism, as well as the well-known tumor-protective effects of several dietary factors, such as folates, vitamine B12 and co-balamine, have been linked to the metabolism of methionine. Evidence presented in this application implicate, for the first time, p53 and SUMO as potential modulators of the metabolism of methionine, via ARD/ADI1. Regulation of this pathway could in turn alter susceptibility to dietetic factors, affect SAM levels, and consequently, lead to epigenetic changes that provide a cancer-predisposing milieu. The scope of this exploratory application is the testing of these hypotheses and to understand the molecular mechanisms by which p53 and SUMO regulate the metabolism of methionine. Data gathered with these studies have the potential to identify a novel loop by which the p53 tumor suppressor directly influences cellular responses to nutrients and, thus, cancer predisposition. PUBLIC HEALTH RELEVANCE: Cancer is the manifestation of a series of abnormal events that involve both genetic and epigenetic changes. Epigenetic changes are achieved via modifications of the activity of proteins that are in intimate contact with the DNA, such as chromatin, and via methylation of the DNA itself. A variety of regulatory proteins that produce such changes, including DNA methyltransferases, methyl-CpG binding proteins, and chromatin remodeling factors, utilize a bio-product of the metabolism of the amino acid methionine, called SAM, for their reactions. It is now well recognized that changes in epigenetic events account for the effects of many environmental and dietetic factors on cancer predisposition. An abnormality of methylation reactions that involve both DNA and proteins is a hallmark of most cancers. We have identified a potential feedback-loop by which a prototypical tumor suppressor, p53, might directly influence cellular responses to nutrients and, thus, cancer predisposition. The general scope of this application is to develop a better understanding of the link between tumor-suppressor pathways, diet, and post-translational modifications that have the potential to influence epigenetic changes.