Grant: Project Grant

PARP inhibitors (PARPi) and agents that target the DNA damage response (DDR) have been shown to be useful for the treatment of a number of tumor types. In some cancers they can be used as an alternative to chemotherapy. In others, these drugs can be used to prolong the time until the disease returns. PARPi target PARP molecules found in cells, which helps cells repair themselves from damage to their DNA. PARPi work by blocking PARP1 enzyme from synthesizing a biopolymer called PAR. Blocking PAR synthesis will eventually lead to the accumulation of unrepaired DNA lesions and cell death. PARPi are effective in patients with BRCA mutations. The BRCA gene is a DDR-associated gene that can be faulty in patients. Patients with a BRCA mutation have an increased risk of developing some cancers. Because studies have shown the usefulness of inhibiting PARP1 in killing breast, ovarian, prostate and pancreatic cancer cells, understanding the interplay between PARP1 and proteins involved in the DNA damage repair is critical to improve clinical outcome. The project aims at understanding how a new family of DDR regulators that we discovered, called ZIPPs, play a pivotal role in determining the sensitivity of cancer cells to PARPi and other DDR-targeting drugs. Agents that target DDR are similar to PARPi except they target other molecules involved with DNA damage or repair. The concept of DDR regulation by ZIPPs emerged from our recent research on a group of PAR-binding proteins [Genes Dev 2019*, PNAS 2021*, NAR 2023*] that impact PARPi resistance or sensitivity [NAR Cancer 2023*]. Understanding the role of ZIPPs will provide new perspectives and opportunities to increase PARPi response and may identify potential strategies with drugs that target the DDR. *Papers from our group.