Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. MCC has two etiologies caused by integration of Merkel cell polyomavirus or by extensive ultraviolet (UV) damage to the tumor genome. In nonviral MCC, the p53 gene is mutated while in most viral MCC tumors, the p53 gene is wild type and is controlled by the MDM2 ubiquitin ligase. Previous research from the DeCaprio Lab determined that inhibitors of the MDM2 – p53 interaction can elicit a rapid and sustained p53 response in MCC cells with wild-type p53. The p53 response can lead to apoptosis and cell death (Park et al., PNAS, 2019, Ananthapadmanabhan et al., JCI Insight, 2022). While a limited number of p53 downstream target genes in MCC have been identified and validated, the full spectrum of p53 targets in MCC has not been identified. To investigate the hypothesis that MDM2 inhibition in viral MCC leads to rapid activation of p53 leading to transactivation of downstream target genes that contribute to apoptosis and cell death and chromatin occupancy of p53 in MCC includes known p53 target genes and a distinct set of genes unique to MCC, I will test several commercially available anti-p53 antibodies to identify the antibodies that work in the CUT&Tag assay and compare the chromatin occupancy of p53 across various virus positive MCC cell lines as compared to MDM2 amplified cell lines or other cancer cell lines expressing wild-type p53 and correlate changes in p53 downstream target genes with chromatin occupancy. The projected impact of this research is that it may potentially identify new p53 targets in MCC, allowing for greater understanding of the carcinoma and contribute to the development of new therapeutics that could benefit the lives of many patients suffering from this disease.