Grant: Project Grant

Inhibition of poly(ADP-ribose) polymerase (PARP) proteins, which cells use in a variety of DNA damage repair mechanisms, is a promising therapy for cancers. Because cancer cells often have preexisting defects in DNA damage repair pathways, the inhibition of PARP can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. This is called synthetic lethality. The concept of synthetic lethality is that cell death occurs when two separate mechanisms for repair of defective DNA are present in a cell and both are incapacitated. Our project aims to discover and characterize previously unknown proteins that can affect synthetic lethality, notably through modulation of the DNA repair machinery. All organisms have evolved mechanisms that allow the maintenance of genomic integrity. The consequences of damaged DNA, and especially double-strand breaks, may be disastrous and lead to cancer if left unrepaired. All organisms can suffer DNA damage, during normal cellular processes or as a consequence of DNA damaging agents such as UV and ionizing radiation. Conversely, treatment of cancer cells with chemotherapy and radiotherapy aims at damaging the DNA of cancer cells to kill them specifically. The present project aims at understanding how cells detect and repair DNA double-strand breaks. Particularly, we want to understand how poly(ADP-ribose), a molecule which is synthesized at sites of damaged DNA, orchestrates the detection and repair of broken DNA. Specifically, we will analyze how PARPs affect the pathways by which double-strand breaks are repaired. Because studies have shown the usefulness of inhibiting poly(ADP-ribose) synthesis in killing breast, ovarian and pancreatic cancer cells, understanding the interplay between poly(ADP-ribose) and proteins involved in DNA damage repair is critical to design better cancer therapies and to improve clinical outcome.