How cells ensure precise genome duplication

Before a cell divides, it must duplicate its DNA, so that each of the resulting daughter cells has a complete copy. Errors in this process (mutations) are a cause of many diseases, including cancer. Our lab studies the strategies that cells use to ensure that the copying of DNA (‘DNA replication’) is as precise and accurate as possible.


During S phase of the eukaryotic cell division cyclethe entire genome must be faithfully duplicated. 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. To achieve this the eukaryotic cell cycle is divided into two non-overlapping phases. Early in the cell cycle, future replication origins are “licensed” by loading double hexamers of the MCM2-7 proteins. During S phase, MCM2-7 at licensed replication origins are activated to initiate bidirectional replication forks. The ability to license new replication origins is abolished prior to entry into S phase so as to ensure that no segments of DNA are replicated more than once.  Replication forks can irreversibly stall when they encounter unusual structures on the DNA, such as DNA damage or tightly bound protein–DNA complexes.

The inability to license new origins after the onset of S phase therefore provides a challenge for the cell to fully replicate the genome using its finite supply of licensed origins.

We take a multi-disciplinary approach to understanding how DNA replication is controlled to ensure that the genome is precisely duplicated in each cell cycle with a minimum of errors. We are interested in understanding how both licensing and initiation are regulated, and how mistakes made in these processeslead to irreversible genetic modifications.Since many early stage cancer cells have lost the ability to correctly regulate DNA replication we are also interested to understand what happens when these control processes go wrong, and how cells respond to the under- or over-replication of chromosomal segments.