Grant: Project Grant

This research aims to enhance our understanding of how DNA double-strand breaks (DSBs) are repaired, focusing on a process called DNA resection. By exploring the mechanisms involved, particularly the role of a key enzyme called PARG (poly(ADP-ribose) glycohydrolase), we hope to identify new approaches for cancer treatment. DSBs, if not properly repaired, can lead to harmful chromosomal changes, contributing to cancer development. One of the early events in DSB repair involves the enzyme PARP-1, which adds a molecule called PAR to proteins, signaling the need for repair. PARG removes these PAR molecules, a step believed to facilitate repair, but its precise role, especially in handling PAR-DNA hybrids, remains unclear. Our research has shown that PARG controls DNA resection, a critical step in determining the repair pathway. Inhibiting PARG can lead to excessive DNA resection, causing genomic instability. We will investigate how PARG's DNA binding and PAR removal activities influence DNA resection, examine its cellular role in handling PAR-DNA hybrids, and identify factors that lead to overresection. Additionally, we aim to explore synthetic lethal strategies that could target cancer cells resistant to current treatments. Our team, comprising experts in DNA repair, PAR biology, chromatin dynamics, and crystallography has made significant progress in understanding these processes. With the support of collaborators specializing in cancer models, proteomics, and PARylation we are well-prepared to uncover how targeting PARG could improve cancer therapy, especially for patients who develop resistance to current PARP inhibitors. This research could lead to new, non-traditional therapeutic options in the fight against cancer.