DNA replication forks and checkpoints

Every time a cell copies its DNA, the machinery doing the copying can jam—and when it does, a molecular alarm system must decide whether to fix the jam or let the cell die. This project aims to understand exactly how that alarm system works. The problem is that scientists know the parts of this DNA replication checkpoint—the proteins involved and the general shape of the signalling pathway—but not how it detects such a wide variety of jams (called replication fork stalls) and responds through a single common route. Without this understanding, it is impossible to predict when the system fails, which is a hallmark of cancer cells. This is fundamental science with no immediate practical application. The researchers will use a test-tube system that rebuilds DNA replication from purified proteins, adding checkpoint components and custom DNA templates to watch the activation process in molecular detail. They will also investigate a newly discovered protein, HLTF, whose loss paradoxically prevents permanent fork arrest—suggesting it creates a toxic intermediate that the checkpoint normally blocks. Understanding this mechanism could eventually reveal why some cancers become resistant to chemotherapy drugs that deliberately stall replication forks.