Bell Lab

The Bell Lab is studying the assembly of the multi-enzyme replisomes that replicate animal chromosomes and how these events are regulated during the cell cycle to ensure genome maintenance.

Chromosomes are the permanent repositories of the information that directs cell function. Each chromosome consists of a single DNA molecule with an array of associated proteins. Each time a cell divides it must accurately and completely replicate the DNA at the foundation of each chromosome and reassemble the proteins that interpret this essential cellular blueprint. Remarkably, during an average human lifetime this process accurately synthesizes trillions of miles of DNA. Inaccurate, incomplete, or excessive DNA replication can lead to cell death, developmental abnormalities, or cancer. Consistent with its critical role, chromosome duplication is carefully coordinated with cell division.

Studies focus on the events that occur at the starting points of chromosome duplication, called origins of DNA replication. These DNA sequences are found at multiple sites on each eukaryotic chromosome and direct the assembly of a bidirectional pair of replication machines, or replisomes, that replicate the DNA on both sides of the origin. Each replisome must coordinate the activity of multiple enzymes, including a DNA helicase, three DNA polymerases, and an RNA polymerase. The events that occur at origins can be broken down into four steps: origin selection, helicase loading, helicase activation, and replisome assembly. To maintain proper chromosome numbers, dividing cells separate origin selection and helicase loading from helicase activation and replisome assembly. This separation ensures that each origin of replication can initiate replication only once per cell division, preventing rereplication of the genome.