Scientists Uncover a Novel Enzyme, PUCH, Vital in Countering Genomic Parasites

In a recent breakthrough, scientists have identified an enzyme named PUCH, which plays a pivotal role in restraining the proliferation of parasitic DNA sequences within our genome. This revelation holds the potential to deepen our comprehension of the mechanisms by which our body identifies and combats both internal adversaries, such as genomic parasites, and external threats, including viruses and bacteria.

Professor René Ketting’s research team at the Institute of Molecular Biology (IMB) in Mainz, Germany, in collaboration with Dr. Sebastian Falk’s group at the Max Perutz Labs in Vienna, Austria, has unveiled a novel enzyme, PUCH, with a crucial function in preventing the dissemination of parasitic DNA within our genomes. This groundbreaking discovery offers the prospect of enhanced insights into our immune systems’ ability to recognize and counteract pathogens, thereby bolstering our defenses against infections.

Constantly besieged by myriad foreign intruders, such as viruses and bacteria, our cells rely on the immune system—a specialized contingent of cells dedicated to detecting and neutralizing these invaders—to safeguard our health. However, the threats our cells face extend beyond external adversaries; they also encounter internal challenges.

A substantial 45 percent of our genome is occupied by thousands of genomic parasites, specifically repetitive DNA sequences known as transposable elements (TEs). These TEs, ubiquitous in all organisms, lack a defined function but possess the potential for harm. Aptly referred to as “jumping genes,” they have the ability to replicate themselves and integrate into new locations within our DNA.

This poses a significant problem, as it can lead to mutations that disrupt normal cell function or even trigger cancer. Consequently, nearly half of our genome is embroiled in a relentless battle with TEs, which seek to proliferate while our cells strive to contain their spread.

How, then, do our cells confront these internal adversaries? Thankfully, our cells have evolved a genomic defense mechanism, comprising specialized proteins tasked with tracking down TEs and impeding their replication. In a recently published paper in Nature, René Ketting, Sebastian Falk, and their research teams unveil their discovery of PUCH—a hitherto unknown enzyme that plays a pivotal role in this genomic defense system. Their research reveals that PUCH is instrumental in generating small molecules called piRNAs, which detect TEs in their attempts to “jump.” Subsequently, they activate the genomic defense system, preventing TEs from integrating into new locations within our DNA.

While the researchers initially detected PUCH in the cells of the roundworm C. elegans, a simple invertebrate often utilized in biological research, their findings may illuminate the workings of our own immune system. Notably, PUCH exhibits distinctive molecular structures known as Schlafen folds.

Schlafen fold-containing enzymes are also present in mice and humans, where they appear to play a role in innate immunity—the body’s initial defense against viruses and bacteria. For instance, certain Schlafen proteins impede viral replication in humans. Conversely, some viruses, like monkeypox viruses, may employ Schlafen proteins to counter the cell’s defense system. René Ketting suggests that Schlafen proteins could potentially have a broader, conserved role in immunity across various species, including humans.

“Schlafen proteins may represent a previously undiscovered molecular bridge between immune responses in mammals and deeply conserved RNA-based mechanisms that regulate TEs,” notes Ketting, who also holds the position of Professor of Biology at Johannes Gutenberg University Mainz (JGU). If this holds true, Schlafen proteins might constitute a shared defense mechanism against both external adversaries such as viruses and bacteria and internal threats like TEs.

Sebastian Falk adds, “It’s conceivable that Schlafen proteins have been repurposed into enzymes that safeguard cells from infectious DNA sequences, such as TEs. This discovery has the potential to significantly impact our understanding of innate immune biology.”

Reference: “piRNA processing by a trimeric Schlafen-domain nuclease” by Nadezda Podvalnaya, Alfred W. Bronkhorst, Raffael Lichtenberger, Svenja Hellmann, Emily Nischwitz, Torben Falk, Emil Karaulanov, Falk Butter, Sebastian Falk and René F. Ketting, 27 September 2023, Nature. DOI: 10.1038/s41586-023-06588-2

Frequently Asked Questions (FAQs) about Genomic Parasites

More about Genomic Parasites

• Nature study on PUCH enzyme
• Institute of Molecular Biology (IMB), Mainz, Germany
• Max Perutz Labs, Vienna, Austria
• Johannes Gutenberg University Mainz (JGU)
• Transposable Elements (TEs) in Genomes