Functional dissection of the archaeal replicative DNA helicase complex

Chromosomal DNA replication in all forms of life requires the complex interplay of a variety of essential and non-essential proteins factors in a temporally and spatially coordinated manner. Understanding how these processes occur in human cells, and how they are regulated, presents a major challenge to modern biology. By using simple model systems such as yeast or archaea, it is possible to gain insights into replication enzyme structure, function and regulation, insights that greatly inform our understanding of the mechanics of chromosome replication in our own cells.
The proposed project focuses on the eukaryal-archaeal CMG complex. This multisubunit complex lies at the heart of the replication machinery, unwinding double-stranded DNA as it is encountered by the moving replication fork. How does the CMG complex perform its function? CMG is made up of Cdc45, MCM and GINS, homologues of all of which have now been identified in archaea. The project will combine genetic and biochemical analysis of CMG helicase structure and function in a model archaeal organism, the halophile Haloferax volcanii. Unlike most archaeal models, this organism is tractable to molecular genetic methods and a wide variety of tools have been developed to facilitate this. The aim of the project will be to characterise biochemically and genetically the interactions that take place between the putative CMG components in this organism. Depending on the results of these studies, it will be possible to perform a more detailed molecular biology analysis of archaeal CMG function in vivo, to initiate a detailed structural or enzymatic analysis of the CMG in vitro, or ideally, both. Taken together, the results of these studies will ultimately offer insights into the biology of chromosome replication in archaea and eukaryotes.
The student will joint a vibrant research group with interests in various aspects of DNA replication and repair in fission yeast and archaeal systems in a brand new multidisciplinary research facility (opened 2012). See http://biology.st-andrews.ac.uk/macneill for details.