PUCH Enzyme Helps Fight Parasitic DNA in Human Genomes, Offers Key in Detecting and Preventing Infections

Millions of pathogens, like viruses and bacteria, constantly attack our cells. To prevent them from making us sick, our body is protected by the immune system, an army of cells specializing in detecting and destroying the invaders. However, our cells are also threatened not only by external invaders but also by enemies from within.

Invasion of Genomic Parasites

About 45% of our genome is composed of thousands of genomic parasites. This includes transposable elements (TEs), which are repetitive DNA sequences found in all organisms but do not have specific functions.

Transposable elements, however, can be dangerous. They are also called "jumping genes" because they can copy and paste themselves into new locations in our DNA. This poses a major problem since it can lead to mutations that can stop cells from working normally, developing cancerous cells. Because of this, almost half of our genome is engaged in a constant war with the other half as transposable elements try to multiply while the normal cells attempt to prevent them from spreading.

Genomic Defense System

Fighting the internal enemies is different from defending the body against outside invaders. Fortunately, the human cells have evolved a genomic defense system composed of specialized proteins that work by hunting down transposable elements and preventing them from replicating.

At the Institute of Molecular Biology (IMB) in Mainz, Germany, a team of researchers discovered a previously unknown type of enzyme called PUCH, which can serve as a key in the genomic defense system. The scientists, led by IMB Professor René Ketting and Dr. Sebastian Falk at the Max Perutz Labs in Vienna, Austria, found that this completely new enzyme plays an important role in creating small molecules known as piRNAs. These molecules can detect transposable elements whenever they attempt to "jump." The piRNAs also activate the genomic defense system to stop the actions of transposable elements before they paste themselves into new locations in our DNA.

PUCH was discovered by the researchers in the cells of the roundworm Caenorhabditis elegans, a simple type of invertebrate often used in biological research. The investigations made by the researchers reveal that PUCH has unique molecular structures called Schlafen folds. Enzymes containing Schlafen folds can also be found in mice and humans, playing a crucial role in innate immunity.

For instance, some Schlafen proteins restrict the replication of viruses in humans. Meanwhile, some viruses, like monkeypox viruses, may also use Schlafen protein to attack the defense system of the invaders. Because of this, Ketting assumes that the Schlafen protein may have a wider, conserved role in immunity in various species, such as humans.

According to Ketting, Schlafen proteins have the potential to represent an unknown molecular connection between immune responses in mammals and deeply conserved RNA-based mechanisms that control transposable elements. They can also represent a common defense mechanism against external invaders like viruses and bacteria and internal enemies like transposable elements.

Ketting added that Schladen proteins have been repurposed into enzymes that defend cells from infectious DNA sequences like transposable elements. The research team believes their discovery may impact our understanding of innate immune biology.