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Maintenance of genome integrity is a dynamic process involving complex regulation systems. Defects in one or more of these pathways could result in cancer. The most important tumor-suppressor is the transcription factor p53, and its functional inactivation is frequently observed in many tumor types. The tumor suppressive function of p53 is mainly attributed to its ability to regulate numerous target genes at the transcriptional level. While the mechanism of transcriptional induction by p53 is well characterized, p53-dependent repression is not understood in detail. Here, we review the manifold mechanisms of p53 as a transcriptional repressor. We classify two different categories of repressed genes based on the underlying mechanism, and novel mechanisms which involve regulation through noncoding RNAs are discussed. The complete elucidation of p53 functions is important for our understanding of its tumor-suppressor activity and, therefore, represents the key for the development of novel therapeutic approaches

One Function—Multiple Mechanisms: The Manifold Activities of p53 as a Transcriptional Repressor