Agnel Sfeir, PhD

Cells use DNA repair systems to fix damage and keep their DNA stable. When these systems fail, it can lead to cancer and make treatment harder. One toxic type of damage is a double-strand break (DSB), where both strands of DNA are cut. In healthy cells, DSBs are usually fixed by a process called homologous recombination (HR). This method is very accurate. Some tumors, especially those with BRCA1 or BRCA2 mutations, lose the ability to use HR. These tumors rely on backup repair methods that are less accurate. One of these is called microhomology-mediated end joining (MMEJ). MMEJ fixes breaks by using short, matching DNA sequences, but it often adds or deletes small sections of DNA.MMEJ depends on an enzyme called polymerase theta (Polθ), which is found at high levels in many cancers. Research shows that BRCA-deficient tumors need Polθ to survive. Because of this, Polθ is now being tested as a drug target, alone and with PARP inhibitors. This project studies how MMEJ helps cancer cells resist treatment. We focus on two key ways. First, MMEJ can create changes that fix BRCA1 or BRCA2, which restores HR and reduces the effects of PARP inhibitors. Second, MMEJ may support the growth of extra circular DNA (ecDNA) that carries cancer genes. This makes tumors grow faster and resist therapy. By understanding how Polθ drives these changes, we hope to find new ways to treat cancer and make current therapies last longer.