Grants awarded

The molecular mechanisms of eukaryotic DNA damage tolerance pathways

Grantholder:

Dr Thomas Guilliam

MRC Laboratory of Molecular Biology

United Kingdom

Life can be viewed as an elaborate mechanism for the replication and propagation of DNA. Cellular division and the reproduction of organisms rely on the accurate duplication of the genome. However, hundreds of thousands of DNA damage events occur in each cell every day and this damage can block DNA replication leading to genome instability and cell death. Cells possess mechanisms to tolerate this damage.

I aim to elucidate the molecular details of each DNA damage tolerance mechanism, and how the choice between different pathways is regulated. I will use reconstitution biochemistry with fluorescence and force-based single-molecule techniques. Reconstituting these mechanisms outside the cell will improve our understanding of the proteins involved and their interplay with the core replication machinery.

My findings will enhance our understanding of how these mechanisms can break down during the development of cancer and how this knowledge can be exploited to treat the disease.