The DNA packed inside every human cell contains instructions for life, written in billions of letters of genetic code. Every time a cell divides, the complete code, divided among 46 chromosomes, must be faithfully copied. This staggering task happens over and over with extraordinary precision.
Decades of research have revealed how dozens of proteins work together to copy chromosomes reliably. Now, Cold Spring Harbor Laboratory (CSHL) President Bruce Stillman and colleagues have compiled these findings into a comprehensive view of the very first step: a “licensing” stage wherein many starting points for DNA replication on all chromosomes are assembled into an essential mechanism called the pre-replicative complex (pre-RC). It’s like a license for life itself.
Stillman has studied DNA replication for more than 40 years. “I’ve focused on understanding one of the most fundamental processes in life,” he says. In humans, the process unfolds billions of times a day. Missteps can increase one’s risk for cancer, autism, and congenital heart disease.
Throughout the 1980s and ‘90s, Stillman’s lab at CSHL uncovered crucial proteins that ensure DNA replication begins when and where it should. One of his earliest collaborators was a postdoc named John Diffley. For many years, Diffley has run his own lab at The Francis Crick Institute . Thanks in part to the two, scientists now know the identities of more than 100 proteins that organisms from fungi to humans need to replicate their genomes. Stillman recently reunited with Diffley to bundle all this knowledge into a neat package. They then brought in University of Utah cell biologist and animator Assistant Professor Janet Iwasa to bring that knowledge to life.
Why would life require an intricate mechanism like the pre-RC? It’s all about efficiency. “In bone marrow alone, about 500 million cells are born every minute, each requiring duplication of over 2 meters of DNA,” Stillman explains. If chromosomes were copied from end to end, this would take months. Instead, cells copy many DNA segments at once. To coordinate, various starting points are marked along each chromosome. Markers are removed as sites are used. New marks cannot be placed until after the cell divides, so each segment only duplicates once per cycle.
Reading this is one thing, seeing it another. Stillman says Iwasa’s animations provide invaluable education tools for biochemistry graduates at any career stage. They’ve already inspired new experiments in his lab, testing how pre-RCs are established in different species. Throughout his long career, Stillman has encouraged colleagues investigating such fundamental processes to “think like a molecule.” His latest publication offers new ways to do just that.
Nature Structural & Molecular Biology
Mechanisms for licensing origins of DNA replication in eukaryotic cells