Our research team has made significant progress in understanding how DNA repair factors fix DNA damage caused by stalled RNA transcription. We discovered that several cancer risk factors suppress genome instability caused by the accumulation of DNA:RNA hybrids. They enzymatically unwind RNA structures that have become trapped in the DNA duplex.
We have now made new discoveries about the role of cancer risk factors in regulating the removal of several physiologically important R-loops. They are particularly linked to IgG class switch regions, specific promoters, splice sites, and telomeres. In cancer, these are major sites of genome instability. As part of this research program, the student will explore the basic biochemical function of enzymes that unwind DNA:RNA hybrids. They will also study the consequences of loss of these DNA interactions on genome stability in cancer pathogenesis, specifically related to mammary and blood cell development and tumour formation.
The most important outcome of this project will be a translatable application of our discovery linking tumour suppressor activity to the prevention of DNA damage caused by DNA:RNA hybrids. Because R-loops play such an important role in genome stability, they are an excellent target for new therapeutic strategies. This is especially true in tumours where normal DNA damage repair pathways are missing or mutated, or R-loop formation is high.