21. 07. 2026
Reading time: 5 minutes
Every cell in our body needs to create an exact copy of its DNA before it divides. This process, called replication, is among the most important cellular processes. Any disruption of it can result in genomic instability and increase the risk of cancer.
A new study published in the prestigious journal Nature Communications (IF 18.1) (open in a new window) focuses on the mechanisms of replication stress induced by oncogenes – genes whose abnormal activation or mutation promotes cancer development. Research teams from the Institute of Molecular Genetics of the CAS, the Faculty of Science at Charles University, the University of Zurich, the University of Bern, and the Institute of Experimental Medicine of the CAS (IEM CAS) collaborated on the study. The IEM CAS was represented by Martin Andrš and Jana Dobrovolná.
What is responsible for replication stress?
During DNA replication, a so-called replication fork, a dynamic Y-shaped molecular structure, moves along the chromosome, unwinds the DNA double helix and creates a new copy of the genetic code. When this movement slows down or stops entirely, a situation termed replication stress, the fragile Y-shaped DNA structure can cause genomic instability and increase the risk of tumour cell formation.
The research team focused on two oncogenes known to cause replication stress. One was mutated HRAS, the other an excessively produced cyclin E1. Both are common oncogenes that drive the progression of many tumours, such as head and neck and ovarian carcinomas. Although it had long been assumed that each of these increases R-loops, DNA transcription intermediates that can act as obstacles to DNA replication, the exact mechanisms underlying this increase and its consequences were unclear.
Issues faced by DNA replication
The authors found that after HRAS and cyclin E1 activation, these R-loops accumulate, especially during the S-phase of the cell cycle, that is when DNA is being replicated. This suggests that they form primarily as a result of the collision between transcription and replication. It is precisely these collisions that are the main source of replication stress.
When the replication fork encounters an obstacle, it can change its shape and kind of invert into a four-way structure, resembling a “chicken foot”. This is a natural defence mechanism that enables the replication fork to be preserved until the cell resolves the issue. However, when this state persists until mitosis, the unresolved replication issues can cause chromosome breakage and gross genomic instability. The rate of DNA replication returned to normal once the scientists prevented the formation of inverted replication forks, and the number of errors during chromosome division also plummeted.
Different mechanisms, similar outcome
Although both oncogenes show similar effects in the formation of R-loops, they do so in different ways. When considering the mutated HRAS, the main factor involved is the production of reactive oxygen species (ROS). DNA replication actively responds to the presence of ROS through the peroxiredoxin 2 oligomer, which slows replication fork progression, resulting in increased transcription-replication interference and errors during cell division. Reducing ROS by antioxidants prevented replication stress and genome instability.
When observing cells with excessive cyclin E1 production, the same mechanism proved ineffective, indicating that this oncogene triggers replication stress in a different way, even though the outcome is similar.
A new perspective on the development of cancer
The results indicate that different oncogenes induce replication stress through distinct mechanisms, yet they lead to the same defects in DNA replication. The study also revealed the mechanisms that help cells resume replication. A better understanding of these processes may contribute to the future development of new approaches to cancer treatment that target replication stress and genetic instability.