Grant: Project Grant

Cancer treatments often exploit weaknesses in cancer cells, such as their inability to repair DNA damage effectively. Poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs, target cancer cells with faulty DNA repair genes, such as BRCA1/2, leaving them unable to repair DNA breaks and causing cell death. However, many cancers develop resistance to these drugs, leading to treatment failure. A protein called MAEA has emerged as a key player in this process. We discovered that MAEA helps protect cancer cells by preventing excessive cutting of damaged DNA ends, a critical step in accurate DNA repair. Without MAEA, DNA damage becomes catastrophic, overwhelming the cell's repair systems. This study investigates how MAEA controls DNA repair under stress. Using lab-grown cancer cells, the team discovered that MAEA collaborates with proteins involved in DNA repair and marks others for removal, ensuring that damaged DNA is repaired correctly. When MAEA is absent, cells struggle to stabilize stalled DNA replication forks and repair DNA breaks, making them vulnerable to chemotherapy. The research aims to identify MAEA targets and determine how its loss creates weaknesses that could be targeted with new therapies. By combining advanced techniques like protein analysis and drug testing, the team will explore how blocking MAEA or its partners could enhance the effectiveness of existing treatments, particularly in cancers resistant to PARP inhibitors. This could lead to personalized therapies where patients with low MAEA levels receive tailored drug combinations to exploit these vulnerabilities. Ultimately, understanding MAEA's role may unlock strategies to overcome treatment resistance, improving outcomes for ovarian and other hard-to-treat cancers.