Defence against the enemy within: Scientists discover a new enzyme that helps cells fight genomic parasites

Rene Ketting (© IMB Mainz)


The research team of René Ketting at the Institute of Molecular Biology (IMB) in Mainz, Germany, has identified a new enzyme called PUCH, which plays a key role in preventing the spread of parasitic DNA in our genomes. These findings may also reveal new insights into how our bodies detect and fight bacteria and viruses to prevent infections.

Our cells are under constant attack from millions of foreign intruders, such as viruses and bacteria. To keep us from getting sick, our bodies have an immune system – a whole army of cells that specialises in detecting and destroying these invaders. However, our cells face threats not only from external enemies but also from within.

An amazing 45% of our genome is comprised of thousands of “genomic parasites” – repetitive DNA sequences called transposable elements (TEs). TEs are found in all organisms but have no specific function. They can, however, 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 normally or to become cancerous. As such, almost half of our genome is engaged in a constant guerrilla war with the other half: TEs seek to multiply, while our cells try to prevent them from spreading.

How do our cells combat these internal enemies? Fortunately, our cells have evolved a genomic defence system of specialised proteins whose job is to hunt down TEs and prevent them from replicating. In a new paper published in the journal Nature, René Ketting and Sebastian Falk (Max Perutz Labs, Vienna, Austria) and their research teams report their discovery of PUCH – a completely new, previously unknown type of enzyme, which is key to this genomic defence system. They found that PUCH plays a crucial role in producing small molecules called piRNAs, which detect TEs when they attempt to “jump” and activate the genomic defence system to stop them before they paste themselves into new locations in our DNA.

The researchers discovered PUCH in the cells of the roundworm (C. elegans) – a simple invertebrate often used in biological research. However, the findings may also shed light on how our own immune system works. PUCH is characterised by unique molecular structures called Schlafen folds. Enzymes with Schlafen folds are also found in mice and humans, where they appear to play a role in innate immunity – the body’s first line of defence against viruses and bacteria. For example, some Schlafen proteins interfere with the replication of viruses in humans. On the other hand, some viruses (e.g. monkeypox viruses) may also use Schlafen proteins to attack the cell’s defence system. René suspects that Schlafen proteins may have a wider, conserved role in immunity in many species, including humans.

“Schlafen proteins may represent a previously unknown molecular link between immune responses in mammals and deeply conserved RNA-based mechanisms that control TEs”, he says. If so, Schlafen proteins may represent a common defence mechanism against both external enemies (viruses and bacteria) and internal ones (TEs). Sebastian continues: “It’s conceivable that Schlafen proteins have been repurposed into enzymes that protect cells from infectious DNA sequences, such as TEs. This discovery may profoundly impact our understanding of innate immune biology”.

Further details

Further information can be found at www.nature.com/articles/s41586-023-06588-2

René Ketting is a Scientific Director at the Institute of Molecular Biology (IMB) and a Professor of Biology at Johannes Gutenberg University (JGU) Mainz. Further information about research in the Ketting lab can be found at www.imb.de/ketting.

About the Institute of Molecular Biology gGmbH

The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de

Boehringer Ingelheim Foundation

The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its funding programmes Plus 3, Exploration Grants and Rise up!, the Foundation supports excellent scientists during critical stages of their careers. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB) and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.boehringer-ingelheim-stiftung.de/en

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