For the first time, scientists have shown that a major protein acts as a direct block in multiple stages of DNA replication, improving our understanding of how cancer develops. 

Researchers studied the fundamental mechanics of DNA replication in yeast, particularly looking at the role of telomeres. By studying DNA replication in a test tube, the team found that an essential protein can block multiple levels of the accurate copying of DNA, which is known to contribute to the development of cancer. Telomeres are short, repetitive sequences of DNA found at the end of chromosomes. Healthy, normal cell division is carefully controlled and telomeres have an important function, acting like a protective cap during each cell division. Without telomeres, our DNA would degrade with each cell cycle, subsequently becoming unstable with increased chance of developing cancerous mutations. 

Unpicking the processes of DNA replication

By using an existing test tube model developed for budding yeast, scientists at The Institute of Cancer Research, London and the Francis Crick Institute were able to unpick the underlying processes of DNA replication in detail.

The study showed that the major telomere binding protein, Rap1, and not telomere DNA itself, mostly inhibits accurate DNA replication and it does this on multiple fronts. If DNA is not replicated accurately, this can lead to genomic instability, a contributing cause of cancer development. By studying a pure test tube system, the scientists saw that telomere DNA alone did not strongly affect DNA replication. By adding Rap1 to this system, however, they saw a very strong effect. The research is published in the journal Nucleic Acids Research and funded by a Cancer Research UK Career Development Award, the Francis Crick Institute, Wellcome, and the European Research Council (ERC).

Historically, researchers used this budding yeast system as a template to understand standard DNA processes. The use of this system in understanding the role of telomeres in DNA replication represents an important basis for the ICR’s research into fundamental cancer biology. Scientists at the ICR can now build on this study to understand the molecular detail of how telomeres are successfully inherited during each cell division cycle. 

Next steps

Now that scientists have used the system to understand the role of telomeres in budding yeast DNA replication, they now hope to develop this insight to understand how telomeres work in human cells.  

Dr. Max Douglas, Telomere Biology Team Leader at The Institute of Cancer Research, London and one of the authors of the study, said:

“Telomeres are completely intertwined with the development and progression of cancer at multiple levels. If you fail to copy telomeres, you can end up losing them from the ends of the chromosomes. This drives genome instability, which is a major cause of cancer.

“We found that telomere DNA has no real effect, or a very weak effect on DNA replication. Proteins have a strong effect and they are affecting multiple, separate events during the replication process. This is specifically a problem on the lagging strand. Longer term, this should help us understand how telomeres can become lost during DNA replication, which in human cells can drive a cell towards becoming cancerous.”