Grant: CIHR Fellowship

For each of your trillions of specialized human cells to function, they need to express genes. In every cell, every second, a unique set of DNA-encoded genes will be read, and a complementary molecule called RNA will be created via a process called transcription. That transcript is used to build proteins, which do all of the work inside a cell. However, despite being necessary for life, gene transcription is dangerous. It forces the double-stranded DNA helix to unwind, so that one strand can be read and used as the template for the newly-synthesized RNA. This leaves the other DNA strand exposed, vulnerable to accidental damage and mutation, which can then cause diseases such as cancer. Usually, cells finish transcription quickly, remove the RNA molecule, and re-join the two DNA strands to re-make the stable helix. Sometimes, however, the RNA molecule remains attached to its template DNA, leaving the opposite DNA strand exposed and forming a structure called an R-loop. Aberrantly stable R-loops cause DNA damage, trigger inflammatory signalling, and ultimately lead to cancer or cell death. Since R-loop formation is dependent on gene transcription, this means the vulnerability will be specific to certain specialized tissues or cell types, offering a potential therapeutic window to stop R-loop-driven cancer before it starts. However, we currently do not know what makes a particular strand of RNA more likely to become a pathologically stable R-loop, limiting our ability to predict and protect against this basic cellular vulnerability. My work will systematically check various features of the RNA molecule, looking for physical characteristics that cause the sequence to become aberrantly stable when expressed in human cells. Uncovering those RNA-based features that promote tissue-specific DNA damage will help us to understand the origins and development of many types of cancers and degenerative disease, impacting health outcomes both in Canada and on a global scale.