Chromosome replication is a key event in the eukaryotic cell division cycle. During S phase the entire genome must be faithfully duplicated with the minimum of errors. The many thousands of replication forks involved in this process must be co-ordinated to ensure that despite the very large quantities of DNA involved, no section of DNA is left unreplicated and no section of DNA is replicated more than once. Cells achieve this by having a distinct stage that occurs prior to S phase when replication origins are "licensed" for replication. At the onset of S phase, replication forks are initiated only at these licensed replication origins.
As initiation occurs at each origin, the licence is removed, thereby ensuring that it fires only once in each cell cycle. Mistakes made in this process may cause irreversible genetic modifications that could ultimately lead to the cells becoming cancerous. Many early stage cancer cells have lost the ability to correctly down-regulate the licensing system, suggesting that it is an important control system for cancer cells to evade.
The aim of our work is to understand at a molecular level the way that chromosome replication is regulated, and to apply this knowledge to improving the diagnosis and treatment of cancer. Much of our work involves cell-free extracts that support all the nuclear events of the cell cycle and which provide a powerful system for studying this process biochemically.
Current research projects are addressing:
- how the licensing system is regulated at different stages of the cell division cycle;
- how the Cdc7 and cyclin-dependent kinases trigger the initiation of DNA replication;
- the way that replication is co-ordinated with other cell cycle events; and
- how replication origins are physically organised on chromosomal DNA.
