Discovering Novel Chemosensitizing Drugs Targeting Dicer Protein

Undergraduate: Sulgi Kim

Faculty Advisor: Scott Hammond
Department: Chemistry

---

Dicer is a protein that broadly serves two functions: generates short non-coding RNAs (siRNAs and microRNAs), and recruit DNA damage response (DDR) factors for DNA repair. Human Dicer is a large multi domain protein about 200,000 Daltons in size 1. This protein serves a critical for RNA interference pathways; specifically for regulating post-transcriptional gene silencing. The protein synthesizes siRNAs and microRNAs by cleaving the precursors (dsRNA and pre-microRNA). The siRNA and microRNA then complementally bind to mRNA to alter translation or degrade mRNA all together. The Dicer protein also serves an important role in DNA damage response (DDR). Research shows that Dicer, Drosha, and ddRNAs are essential for recruiting DDR factors and amplify DDR signaling in response to the DNA damage

The long-term goal of our research is to discover small molecules that inhibit Dicer protein translation, also determine molecules that alter Dicer¿¿¿s cleavage activity. By inhibiting Dicer, this will increase the spontaneous DNA damage in cancerous cells, which will reduce tumor growth and also increase the cell¿¿¿s sensitivity to chemotherapy drugs. However siRNA are not deliverable to the body and most of the tissues, making Dicer inhibition difficult. Therefore small molecules that alter Dicer¿¿¿s cleavage activity will be used to deliver to the body tissues. Using this strategy, the Dicer protein activity will be reduced and increase the cell¿¿¿s sensitivity to the chemotherapy drugs.