Molecular mechanisms of DNA synthesis by the human replisome

Every time a human cell divides, it must duplicate six billion DNA letters with near-perfect accuracy—and the molecular machine that does this work is still poorly understood. This project aims to map, in atomic detail, how the human replisome—the multi-protein assembly that copies DNA—actually operates. Current knowledge of DNA replication comes mostly from bacteria and yeast, but human cells have a more complex system. Defects in this machinery cause genetic instability, which drives cancer, developmental disorders, and degenerative diseases. Without a clear picture of how the human replisome works, researchers cannot fully understand why it sometimes fails. This is fundamental science. There is no immediate clinical application. The goal is to produce a high-resolution description of DNA synthesis at the moment when the genome is most vulnerable—during replication. Such a description would provide the structural and mechanistic foundation for future work on replication errors, cancer mutations, and inherited genomic disorders. Past fundamental research on DNA replication enzymes, for example, directly enabled the development of polymerase chain reaction (PCR) and antiviral drugs that target viral polymerases. A deeper understanding of the human replisome could similarly open unexpected avenues for diagnostics or therapeutics, but that is not the aim of this grant.