Blocking the DNA triplication by a newly discovered protein

This is a previously unidentified natural “anti-failure” mechanism in the DNA replicating process.

DNA is copied when a cell divides, giving the two daughter cells the identical genetic makeup as the parent cell. This indicates that the body copies its DNA molecule millions of times per day, performing a molecular miracle. It is a very precise task performed by certain proteins and incorporates defence mechanisms against mistakes that may cause illnesses like cancer.

Recently, Juan Méndez and his colleagues in the DNA Replication Group at the Spanish National Cancer Research Centre (CNIO) have identified one of these anti-failure mechanisms. The foundation of it is a protein that makes sure DNA is duplicated only once as it should be instead of twice or more.

Over-replication of a DNA region causes breaks in the molecule and increases the possibility that a gene related to cancer will be overexpressed if it is located in the over-replicated region. This overexpression would have a detrimental effect on the cell’s ability to function and could be the beginning of a cancer.

Therefore, avoiding excess replication prevents DNA damage and reduces the chances of oncogenes being amplified.

Juan Méndez

The structure of the DNA molecule is double-helical. The replication mechanism uses each of the two strands of the helix as a template to create two new double helices before copying it. The procedure takes hours to complete. Cells replicate (and copy DNA) nearly constantly in tissues that regenerate quickly, such as the skin and intestines.

It’s not an easy procedure. 3 billion chemical components, known as bases the well-known letters A, T, C, and G make up a human DNA molecule. The genetic information, or the instructions that guide the cell to produce a certain protein at a specific time, is made up of the arrangement of these letters.

The disease can develop if the instructions are incorrect for instance if there are mutations. As a result, the organism has evolved many molecular defence systems to ensure error-free DNA copying. The one that scientists at CNIO have recently identified is related to the RAD51 protein. In this instance, its goal is to stop previously copied DNA segments from being replicated again.

DNA copying begins at thousands of sites simultaneously, which are called origins in the jargon. The proteins responsible for copying attach themselves to these origins and start working, acting like micro-machines.

It was previously recognised that there is an early mechanism to regulate excess replication, which keeps origins from activating more than once. But if an accidental second copying operation is launched, the recently identified RAD51-based anti-failure mechanism kicks in.

CNIO researchers noticed that RAD51 attaches itself to the freshly created DNA for a brief period of time. The copying machinery cannot proceed if the copying process is unintentionally restarted because its presence on the newly formed DNA, which is now used as a template for copying, creates a physical barrier.

Scientists at CNIO noticed that RAD51 attaches itself to the freshly created DNA for a short while. The existence of the copying process on the new DNA, which is now a template for copying, creates a physical barrier that prevents the copying machinery from moving further if the process is unintentionally restarted.

We observed that RAD51 acts as a second brake on DNA re-replication.

RAD51 prevents genomic duplications that could arise from re-activated origins.

Sergio Muñoz

“DNA re-replication could fuel carcinogenesis by promoting aneuploidy [an incorrect number of chromosomes in the cell] and the formation of heterogeneous cell populations that enhance the adaptability of tumour cells,” the authors write in their paper in The EMBO Journal.

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As there is a higher chance of over-replication in pre-tumoral lesions, the protective function of RAD51 could be especially crucial.

Source: CNIO News

Journal Reference: Muñoz, S., Blanco-Romero, E., González-Acosta, D., Rodriguez-Acebes, S., Megías, D., Lopes, M., & Méndez, J. (2024). RAD51 restricts DNA over-replication from re-activated origins. The EMBO Journal, 1-22.

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