Each of the cells in our body has approximately 2 meters of DNA that needs to be accurately copied every time a cell divides. Mistakes that occur during DNA copying are a major contributing factor towards the development of genetic diseases, cancer and early aging. DNA damage is one of the main causes that prevents cellular DNA being copied properly and can occur either through normal processes during cell growth or can be caused by exposure to radio/chemotherapy or environmental toxins. Excessive DNA damage is extremely toxic, and this forms the basis for why radio- or chemotherapy is used to kill tumour cells. However, cells have evolved complex mechanisms to recognise and repair DNA damage so that the DNA can be copied without any errors.
When DNA is being copied, this is carried out by many proteins that work together as part of a big machine, called the replisome, to unzip, copy and rezip the entire DNA molecule. When the replisome finds damaged DNA, the copying process stops. If the DNA damage is not repaired properly and copying restarts, this can cause chromosomes to break and cells to die. However, when the replisome meets DNA damage, cells have developed an elegant process that pauses the copying process and allows the replisome to back track so that the DNA repair machinery can repair the damage. This is called replication fork (because as the DNA is unzipped and copied it looks like a ‘fork’) reversal. Replication fork reversal is a vital process for the repair and restart of DNA duplication, but represents a period of vulnerability. If the replisome and reversed replication fork are not stabilised and protected, the replisome can fall off and the newly copied DNA can be cut into pieces by proteins called nucleases. This can lead to the breaking or loss of chromosomes and increased mutations, all of which are known to contribute to human diseases.