Grant: Operating Grant

Human cells suffer DNA damage during normal cellular processes or as a consequence of exposure to DNA damaging agents such as ionizing radiation and UV. Cells have evolved mechanisms to detect DNA damage and repair lesions which could otherwise lead to cancer if left unrepaired. However, in the presence of large amounts of DNA damage, the cell may instead undergo a form of suicide, termed apoptosis, if it detects too much damage and cannot repair all of it properly. Treatment of cancer by chemotherapy and radiotherapy is actually taking advantage of the cell's ability to commit suicide. Chemotherapeutic agents and ionizing radiation both aim at damaging the DNA of cancer cells sufficiently to trigger their death. However, many cancer cells have altered their biology to circumvent cell death and therefore, the biochemistry of these cells is unique. This project aims at understanding how cancer cells sense that there is too much damage to repair and how they trigger death signals. Specifically, we want to understand how PARP-1, a protein that rapidly detects DNA damage, and PAR, a molecule synthesized by PARP-1 at sites of DNA damage, send death signals within the cell, and which protein partners are involved in transmitting these signals. Identifying the molecules involved in death signals and understanding their functions is critical to design better cancer therapy treatments and to improve clinical outcome.