Grant: Operating Grant

Cells of the human body experience and fix DNA damage everyday, a process required to preserve health. This is illustrated in many human diseases, including cancer, which is often caused by errors during DNA repair. Additionally, intentional DNA damage induced by radiation or chemotherapy are often used for cancer therapy, mostly because rapidly dividing cancer cells are very sensitive to high levels of DNA damage. A relatively recent and novel angle of the DNA repair research effort investigates how cells that survive DNA damage can return to normal once the damage is repaired. This is a process called DNA damage response recovery. Our hypothesis is that in some context, the DNA damage response recovery is improperly activated and can interfere with the activity of genes that normally prevent cell growth in the presence of DNA damage. This could explain how some normal cells acquire mutations required for cancer progression, or why some cancer cells can survive DNA damage inflicted during therapy. We also think that the DNA damage response recovery can influence how severely damaged cells communicate with their environment, which has consequences for aging and for therapy-associated side effects. Using normal human cells, we propose to characterize the interactions between the amount of DNA damage, the DNA damage response recovery, the maintenance of proper cell growth arrest, and the ability of the damaged cells to send extracellular damage signals (to communicate). The overall goal of this proposal is to broaden our understanding of how DNA damage signaling is stopped or avoided in humans, with a long-term objective of improving patient care by increasing knowledge about targets that could be used to sensitize cancer cells to therapy-induced DNA damage.