Building the replicative helicase in human cells

All proliferating cells must replicate their genomes before they divide. In human cells, this gargantuan and essential task is performed by macromolecular machines called replisomes, which are built around a DNA helicase called CMG. The catalytic core of CMG comprises a hexamer of MCM proteins, which must be correctly assembled before DNA replication begins. We recently identified a previously unknown pathway for MCM hexamer assembly in human cells, driven by an essential chaperone protein, MCMBP.

We now want to understand the molecular mechanisms of MCMBP-mediated MCM assembly. This student will reconstitute MCM2–7 assembly from purified human proteins and use biochemical, structural, and computational approaches to define how MCMBP facilitates this process and how it is regulated in cells. The student will receive training in advanced biochemical and other experimental approaches within a collaborative and supportive research environment.

This work will shed light on a fundamental and newly discovered feature of eukaryotic DNA replication, with broad relevance to genome stability, human disease, and general principles of protein complex assembly.