Investigating the regulation of DNA replication by ubiquitylation

Every dividing cell needs to duplicate its genome perfectly before cell division. Failure to do so can result in cell death or development of mutations leading to cancer. It is essential therefore to understand the mechanism of eukaryotic DNA replication, how it is regulated in normal cells, how its misregulation contributes to tumorigenesis and how this misregulation can be exploited in the treatment of cancer. The proposed project is focusing on studying how ubiquitylation (post-translational protein modification) regulates chromosomal replication. Recently, we have discovered that poliubiquitylation is essential for a truly enigmatic stage of DNA replication – its termination. This project provides therefore and exciting opportunity to follow up this discovery and unravel the details of its mechanism.

The project will be carried out in two biological systems: cell-free Xenopus laevis egg extract and human immortalised cell lines. The X.laevis egg extract can assemble exogenous DNA into nuclei that undergo a complete round of synchronous replication in vitro. As a cell-free system, it allows easy biochemical analysis of the process of DNA replication. Once thorough mechanistic studies have been performed in Xenopus egg extract the project move to human immortalised cell lines.

For more details of the project please direct informal inquiries to Dr Aga Gambus at: [Email Address Removed]