Reversible modifications to histone proteins play a major role in histone-DNA packaging and ultimately gene expression. The Polycomb Repressive Deubiquitinase (PR-DUB) complex removes one important type of histone modification. Mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase susceptibility to asbestos. We have recently solved the structure of the PR-DUB from Drosophila, which is functionally similar to the human complex. Based on this structure, we will investigate why cancer-derived mutations impair activity of the human PR-DUB, and how PR-DUB activity regulates gene expression from particular regions of the genome. The overall goal of this project is to better understand how the PR-DUB is regulated, to facilitate more informed treatment decisions for affected patients and potentially new therapeutic strategies. More broadly, this work will contribute important insight into the relationship between epigenetics and environmental carcinogens.