Protein-DNA transactions on anaphase DNA bridges

Every time a human cell divides, it must carefully copy and split its DNA to ensure that each new cell receives a complete set of genetic instructions. This process is incredibly precise, but not flawless. In the final stages of cell division, fragile connections called DNA bridges can form between the separating sets of chromosomes. If these bridges are not properly resolved, they can tear, leaving broken DNA behind. This damage can lead to lasting genetic changes and contribute to cancer. To prevent this, cells rely on a set of specialized proteins that detect and dismantle DNA bridges. Key proteins for this process are PICH, BLM, and TOP3A, molecular machines that locate to the bridges and work together to untangle them. In this project, we will investigate precisely how these proteins recogise DNA bridges and how they act on them. Thanks to funding for the next four years, our team will rebuild this system in the lab piece by piece and map out how these molecular machines interact with each other and with DNA. We will also study DNA bridges inside living cells using state-of-the-art microscopy, allowing us to observe these processes in unprecedented detail. We also aim to understand what happens when this system fails, and how that might lead to genome instability and disease. In the long term, this knowledge could open up new ways to target cancer cells that depend on these pathways to survive.