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The role of PRDM1 in epigenetic regulation and tumor suppression

Scott Moore Carlson

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National Institutes of Health (NIH)
The PRDM protein family has been an enigma since its discovery almost twenty years ago. The seventeen human PRDM proteins contain a PR domain with close homology to the SET domain family of lysine methyltransferase enzymes. Despite this similarity, with the exception of PRDM9, no PRDM proteins have well-characterized enzymatic activity. Members of the PRDM family have critical roles during development and many are important tumor suppressors or oncogenes, notably PRDM1 as a suppressor of leukemia and lymphoma, and PRDM16 as an oncogene in leukemia. The PR domain is often critical for tumor suppression or oncogenesis but its mechanism of action is unknown. I have identified PRDM1 as an arginine methyltransferase targeting histone H3 at arginine 17. Mutating a key active site residue reduces the ability of PRDM1 to suppress cancer cell growth in culture. This is a completely unexpected activity because all known arginine methyltransferases belong to a single protein family with little similarity to the PR or SET domains. It raises the possibiliy that arginine methylation is a broader function of the PRDM proteins and that this activity may be critical for their roles in development and disease. This proposal aims to uncover the molecular mechanisms of tumor suppression by PRDM1 methyltransferase activity. In the mentored portion I will investigate the biological effects of PRDM1 activity in cellular models of lymphoma, and test the hypothesis that chromatin modification is the primary biological function of PRDM1. In the independent portion of the award I will test the hypothesis that histone modification by PRDM1 mediates biological effects by recruiting or repelling specific chromatin-binding proteins, and determine whether PRDM1 methylates additional non-histone proteins. The final aim of this work is to determine whether other PRDM proteins also methylate arginine and whether this activity participates in regulating cancer pathways. Training during the mentored portion will focus on techniques in molecular and cell biology. These skills will complement my undergraduate and graduate training in chemistry, mass spectrometry and cellular signaling. Discovering PRDM1 as the first non-canonical arginine methyltransferase opens countless avenues for future work and equips me with a unique direction for my independent research. The training provided by this award will be instrumental in achieving my long-term goal of establishing a research program that investigates how signaling processes and epigenetics establish cellular identify, and how their dysregulation leads to disease.

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