Scientists have discovered an enzyme called PUCH that is critical for stopping the spread of parasitic DNA sequences throughout our genomes. This finding could provide insights into how our bodies recognize and fight internal threats, such as genomic parasites, and external threats, such as viruses and bacteria.
The team of Professor René Ketting from the Institute of Molecular Biology (IMB) in Mainz, Germany, and the team of Dr. Sebastian Falk from the Max Perutz Laboratory in Vienna, Austria, discovered a new enzyme PUCH that prevents the spread of parasitic DNA in our genome. This breakthrough could provide a deeper understanding of how our systems recognize and fight pathogens, helping to fight off infections.
Our cells are constantly under attack by millions of foreign invaders, such as viruses and bacteria. To prevent us from getting sick, our bodies have an immune system—an entire group of cells dedicated to detecting and destroying these invaders. However, our cells face threats not only from external enemies, but also from within.
An astonishing 45% of our genome consists of thousands of genomic parasites, repetitive DNA sequences called transposable elements (TEs). TEs are present in all organisms but have no specific function. However, they can be dangerous. TEs are also called "jumping genes" because they can copy and paste themselves into new locations in our DNA.
This is a major problem because it can lead to mutations that cause our cells to stop working properly or become cancerous. So as TEs seek to reproduce, almost half our genome is constantly engaged in guerrilla warfare with the other half, while our cells try to stop them from spreading.
How do our cells fight these internal enemies? Fortunately, our cells have evolved a genomic defense system composed of specialized proteins that hunt down TEs and prevent them from replicating. In a new paper published in Nature, René Ketting and Sebastian Falk and their research team report their discovery of PUCH—an entirely new, previously unknown type of enzyme that is key to this genome defense system. They found that PUCH plays a crucial role in producing small molecules called piRNAs, which detect TEs when they try to "jump." They then activate the genome's defense system, blocking TEs before they can stick to new locations in our DNA.
The researchers discovered PUCH in cells of the worm Caenorhabditis elegans, a simple invertebrate commonly used in biological research. However, these findings may also shed light on how our own immune systems work. PUCH is characterized by a unique molecular structure called the Schlafen fold.
Enzymes with the Schlafen fold are also found in mice and humans, and they appear to play a role in innate immunity, the body's first line of defense against viruses and bacteria. For example, some Schlafen proteins interfere with human viral replication. On the other hand, some viruses, such as monkeypox virus, may also use Schlafen proteins to attack cells' defense systems. René Ketting suspects that the Schlafen protein may play a broader, conserved role in immunity in many species, including humans.
"Schlafen proteins may represent a previously unknown molecular link between mammalian immune responses and highly conserved RNA-based mechanisms that control TEs," said Ketting, who is also a professor of biology at the Johannes Gutenberg University Mainz (JGU). If so, Schlafen proteins may represent a common defense mechanism, both against external enemies such as viruses and bacteria, and against internal enemies such as TEs.
Sebastian Falk added: "It is conceivable that the Schlafen protein has been reengineered into an enzyme that protects cells from infectious DNA sequences such as TEs. This discovery may profoundly affect our understanding of the biology of innate immunity."