Recombination occurs within minutes of replication blockage by RTS1 producing restarted forks that are prone to collapse

Before a cell can divide to form two new cells, it must duplicate its DNA to ensure the newly formed cells have the same genetic information as the original. This genetic material is made up of two single strands of DNA that are paired to form a double-stranded helix. Certain groups of proteins separate these two DNA strands to form a two-pronged structure known as a ‘replication fork’. This occurs at different points along the length of the DNA double helix. Groups of proteins then travel down the DNA strands, separating them as they go, and using them as templates for making copies of the DNA. DNA replication is finally completed when different replication forks meet and merge. This process does not always occur smoothly because some regions of DNA contain obstacles that impede the movement of the replication machinery. In most cases, the replication proteins briefly stall and then restart. However, occasionally the machinery can fall off the DNA; this event is known as a ‘replication fork collapse’. Nguyen et al. have now used a method called time-lapse microscopy to visualise this process inside a species of yeast—called fission yeast—as it occurs in real time. Fission yeast's genetic material is known to contain a specific site that blocks the replication machinery. Nguyen et al. found that a protein called Rad52 arrives at this specific site within 10 minutes of a replication fork being blocked. This protein enables recovery of the replication fork within an hour via a process known as ‘DNA recombination’. Nguyen et al. also unexpectedly found that the restarted fork is susceptible to further collapse. It is known from previous work that the mechanisms that repair broken DNA and rescue replication forks can also introduce errors into the DNA. This implies that if fork collapse occurs frequently, it can lead to the introduction of numerous errors that can be detrimental to cells. Thus, the rescue of fork collapse is like a double-edged sword; it is required for replication to proceed, but can lead to genetic changes inside cells. The failure to faithfully replicate genetic material drives the development of diseases such as cancer. Therefore, insights gained from Nguyen et al.'s findings may provide an improved understanding of how genetic alterations occur in both normal and cancerous cells.