Funded: February 2024
Funded by: The generosity of LJI Board Director Tom Tullie and the Tullie Family

Cancer cells accumulate more RNA-DNA hybrids than normal cells. My SPARK project explores whether scientists can actually increase these hybrids to kill cancer cells. Cancer cells form RNA-DNA hybrids during gene expression. Normally, a cell’s RNase H enzymes step in to prevent hybrid buildup. I aim to block these enzymes and force cancer cells to accumulate RNA-DNA hybrids.

I began by using bone marrow cells from a mouse model of acute myeloid leukemia, and I found higher levels of RNA-DNA hybrids in these cancer cells. I then used CRISPR gene-editing techniques to delete RNase H genes and increased these hybrids. I found that this change caused the cancer cells to stop growing within six days.

My analysis showed that cancer cells without RNase H enzymes showed more DNA breaks, indicating that RNA-DNA hybrids cause harmful DNA damage—which spells trouble for a cancer cell. Mapping these breaks revealed they occurred at genomic enhancers, which regulate gene expression. Going forward, I am testing two drugs that inhibit RNase H enzymes on cancer cells and in mice with leukemia. This approach could lead to new cancer treatments that take advantage of RNA-DNA hybrids to kill cancer cells.