ABSTRACT Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to many traditional therapies. One recent discovery in this cancer is high frequency mutation of SETD2, a histone methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 (H3K36me3) trimethylation mark on actively transcribed genes. Our two groups have in parallel made a series of very exciting discoveries related to a new role for the SETD2 methyltransferase as a tumor suppressor required for genomic stability. First, we observed that loss of the H3K36me3 mark on chromatin impairs repair of DNA double strand breaks. This suggests that loss of SETD2 causes a DNA repair defect, which we hypothesize is due to mis-directed H3K36me3 ?readers? that would normally guide DNA repair machinery to double strand breaks, resulting in genomic instability. Independently, we recently made the exciting discovery of an important novel nonhistone target for the SETD2 methyltransferase: microtubules. These data show that SETD2 methylation of ?-tubulin on lysine 40 (K40Me) of mitotic microtubules is required for proper chromosome segregation and cytokinesis, opening the door for understanding how loss of SETD2 contributes to genomic instability and progression of RCC in a completely new way. We are proposing a multifaceted collaborative project to understand 1) how SETD2 function as a histone and microtubule methyltransferase contributes to genomic stability, and the development of RCC 2) the mechanism linking histone methylation deficits to DNA double strand break repair deficiency, and 3) exploit what we know of this enzyme and the biology of disruption to identify pharmacologic tool compounds, which we will test in vivo for exploring key biological properties of genome maintenance or which hold promise for future targeted therapeutics.