Post-Doctoral positions at the Cancer Research UK London Research Institute, Clare Hall DNA damage and errors made during DNA replication cause cancer. Consequently, cells produce a vast array of different proteins to repair DNA damage and to ensure the fidelity of DNA replication. In order to understand how DNA damage causes cancer, we have been studying a number of systems to learn more about how they repair this damage. There are several positions available for both biochemists and crystallographers at post-doctoral level in two main project areas. Pre-replication complex - initiation of DNA replication Initiation of DNA replication in eukaryotes requires assembly of the pre-replication complex. It has been discovered that DNA replication and repair mechanisms in archeabacteria share many similarities with eukaryotes. We are therefore investigating the pre-replicative complex in archaea as a simplified model for the human complex. We have cloned and expressed the origin recognition proteins (ORC1 and ORC2) and the MCM helicase that together comprise the core of the pre-replication complex. We have already obtained the crystal structure of ORC2 in complexes with different nucleotides and more recently we have determined the crystal structure of the ORC1 protein bound to a replication origin DNA sequence (Science 317, 1213-6 (2007)). The aims of the project are to build on these structures to understand how an entire replication origin (containing ORC, MCM and replication origin DNA) is assembled to initiate DNA replication. These studies will involve a combination of crystallography, biochemistry and single particle cryoelectron microscopy. RecBCD - a key component in DNA repair The RecBCD protein is a key player in the repair of double strand DNA breaks. Using a combination of two helicase subunits and a multi-functional nuclease, the three subunit enzyme complex processes the broken DNA ends and loads them with RecA protein at Chi sites. We have determined the crystal structure of RecBCD complexed with DNA (Nature 99, 13492-13497 (2004)) and are now beginning to undertake biochemical studies based on this structure to understand more about how the enzyme carries out its varied tasks. Future crystallographic studies will be to understand the mechanism of helicase activity by both the RecB and RecD helicase subunits as well as to determine a structure with a Chi site to understand how interaction between this site and the RecC subunit regulates the nuclease activity of the complex and facilitates loading of RecA. To apply for any of these positions send an email containing your CV with the names of 3 referees to Dale Wigley ([EMAIL PROTECTED] ; Website: http://sci.cancerresearchuk.org/labs/wigley).
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