p21WAF1/CIP1 is a transcriptional target of the tumor suppressor p53. p21 protein plays an essential role in cell cycle arrest after ionizing radiation, in certain forms of cancer, autoimmunity and stem cell repopulation. Although pathways that converge on p21 gene transcription are well studied, here we examine the mechanisms that regulate p21 protein stability and their effect on p21 function. In preliminary results we show that UV induces p21 degradation. We show that while low doses of UV induce p21 degradation high doses do not. The ability of UV to induce p21 degradation is dependent on ubiquitin and the F box protein Skp2. Our results show that the cell cycle arrest by UV is p21 independent in contrast to the classical p21 dependent arrest by ionizing radiation. Finally we show that failure to degrade p21 after UV irradiation inhibits both the recruitment of PCNA to chromatin and DMA repair synthesis. In this proposal we will study three aspects of the mammalian cellular response to UV and the critical role p21 plays in this process. First, we will identify the signaling proteins downstream of ATR which induce p21 degradation after low doses of UV. Second, we will identify the kinase which phosphorylates p21 and the phosphorylation site in p21 which dictates Skp2 / p21 binding after UV. We will also examine if Skp2 dependent UV induced p21 degradation is also dependent on Cks1 and allow us to reconstitute UV induced p21 ubiquitination in vitro. Third, we will generate whole animal models in which cellular p21 cannot be ubiquitinated and determine the biological consequences of such a mutation. This will include the effect on cell cycle, checkpoint signaling and skin cancer. ? ?
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