p73 is a member of the p53 tumor suppressor family, which mediates genotoxic stress response by triggering cell cycle arrest and apoptosis. Similar to p53, p73 is maintained at very low levels, but it gets rapidly induced upon genotoxic stress. Mounting evidences demonstrate that p73 is primarily regulated posttranslationally. However, the molecular mechanisms which determine its stability and activity discerningly under normal and stress conditions are still not well understood. Here, we employed a proteomics approach to identify differential interactors of p73 under normal and genotoxic stress conditions. We report here that TRIM28, an E3 ligase, interacts with p73 and targets it for proteasomal degradation under normal conditions. Genotoxic stress-induced phosphorylation of p73 at tyrosine 99 residue by c-abl kinase leads to abrogation of this interaction thereby promoting p73 stabilization. Furthermore, the phosphorylated form of p73 specifically interacts with MED15, which serves as a transcriptional coactivator and leads to activation of proarrest, proapoptotic and anti-metastatic genes. RNAi-mediated abrogation of TRIM28 expression facilitates p73-mediated tumor suppression in mouse tumor models, whereas disruption of MED15 expression abrogates p73 tumor suppressor and anti-metastatic functions. These findings provide new insights into the pivotal role of Tyr99 phosphorylation in determining p73 levels and functions.