Grant: Travel Awards - Institute Community Support

Cancer is the leading cause of death in Canada, accounting for more than 25% of all deaths nationwide. A key characteristic of cancer cells is an increased frequency of DNA rearrangements and mutations collectively known as genome stability. Many cancer treatments take advantage of this vulnerability by introducing additional DNA damage to trigger cancer cell death. Etoposide is a widely used chemotherapeutic that works by targeting topoisomerase II (TOP2), an enzyme which helps untangle DNA during cell division and DNA replication. As part of its activity cycle, TOP2 forms short-lived structures known as TOP2 cleavage complexes (TOP2ccs), where the enzyme is temporarily attached to DNA in order to untangle and relieve DNA stress. Under normal circumstances, these complexes are quickly removed to maintain genome stability. However, etoposide and related drugs prevent the removal of TOP2ccs, causing toxic DNA damage that kills rapidly dividing cancer cells. My research focuses on understanding how cells normally remove these trapped TOP2 complexes, with particular attention to the SLX4 protein. SLX4 acts as a scaffold that coordinates several DNA repair enzymes, ensuring damaged DNA is properly processed. Using cancer cell models, I found that cells lacking SLX4 are highly sensitive to etoposide and accumulate more TOP2ccs during cell division. By uncovering how SLX4 contributes to the removal of TOP2ccs, my work aims to clarify how cells preserve genome stability during division and how these repair processes influence cancer treatment outcomes. This research provides insight into key DNA repair pathways that are disrupted in human cancers, and may ultimately inform strategies to improve the effectiveness of chemotherapy.