LINE-1, a “jumping gene” making up 20% of the genome, invades DNA during cell division using protein-RNA clusters, offering insights into genome evolution and disease.
Viruses are masters of hijacking the cells they infect. To make more copies of themselves, they take over the host’s genetic machinery. In doing so, they often leave behind small traces in our DNA. These traces, known as transposable elements, are tiny pieces of genetic material that act a lot like viruses. They are even simpler in structure, but they also rely on the cell’s own tools to reproduce.
Over time, our bodies have learned to silence most of these foreign sequences. But not all of them are inactive. A few remain restless, earning the nickname “jumping genes” because they can still move around the genome. Among them, one stands out. It’s called LINE-1, short for long interspersed nuclear element 1, and it’s the only one still capable of copying and pasting itself entirely on its own.
LINE-1 works in a clever way. It first creates a copy of itself using RNA, the close chemical cousin of DNA. Then, that RNA is converted back into DNA and inserted into a new spot in the genome. This copy-and-paste process is similar to how the retrovirus HIV operates, which is why LINE-1 is known as a retrotransposon.
In this way, retrotransposons add code to the human genome every time they move, which explains why 500,000 LINE-1 repeats now represent a “staggering” 20 percent of the human genome. These repeats drive genome evolution, but can also cause neurological diseases, cancer, and aging when LINE-1 randomly jumps into essential genes, or triggers an immune response like a virus to cause inflammation.
How LINE-1 Enters the Nucleus
To copy itself, however, LINE-1 must enter each cell’s nucleus, the inner barrier that houses DNA. Now, a new study, published in the journal Science Advances, reveals that LINE-1 binds to cellular DNA during the brief periods when nuclei break open as cells continually divide in two, creating replacements to keep tissues viable as we age. The research team found that LINE-1 RNA takes advantage of these moments, assembling into clusters with one of the two proteins it encodes, ORF1p, to hold tightly to DNA until the nucleus reforms after cell division.
Led by researchers at NYU Langone Health and the Munich Gene Center at Ludwig-Maximilians-Universität (LMU) München in Germany, the work revealed specifically that LINE-1 can only bind to DNA when ORF1p—which can bind to RNA, DNA, and itself in linked copies called multimers—accumulates into clusters of hundreds of molecules called condensates. As more ORF1p molecules build up, they eventually envelop the LINE-1 RNA, which makes more binding sites available for the entire cluster to attach to DNA.
“Our study provides crucial insight into how a genetic element that has come to make up a large part of human DNA can successfully invade the nucleus to copy itself,” says senior study author Liam J. Holt, PhD, associate professor in the Department of Biochemistry and Molecular Pharmacology and the Institute for Systems Genetics at NYU Grossman School of Medicine. “These findings on the precise mechanisms behind LINE-1 insertion lay the foundations for the design of future therapies to prevent LINE-1 replication.”
Implications for Future Research and Therapeutics
The work also suggests that the LINE-1 condensate acts as a delivery vehicle to bring its RNA into proximity of the right sequences (rich in the DNA bases adenine and thymine) on DNA where the retrotransposon tends to insert, say the study authors. Packaged in its condensates, LINE-1 is thought to evade mechanisms that exclude large particles from the nucleus during mitosis as a cellular defense against viruses.
“LINE-1 condensates have a remarkable feature in that their DNA binding ability emerges only when the ratio of ORF1p copies to RNA is high enough in the condensates,” added Dr. Holt. “Moving forward, we will be looking to see if other condensates undergo functional changes as the ratios between their components change.”
Reference: “LINE-1 ribonucleoprotein condensates bind DNA to enable nuclear entry during mitosis” by Sarah Zernia, Farida Ettefa, Srinjoy Sil, Cas Koeman, Joëlle Deplazes-Lauber, Marvin Freitag, Liam J. Holt and Johannes Stigler, 2 May 2025, Science Advances.
DOI: 10.1126/sciadv.adt9318
Along with Dr. Holt, the first study authors were graduate student Farida Ettefa at NYU Grossman School of Medicine and its Institutes for Systems Genetics and Sarah Zernia of Gene Center Munich at Ludwig-Maximilians-Universität (LMU) München in Germany. Also study authors were Cas Koeman, Joëlle Deplazes-Lauber, Marvin Freitag, and co-senior author Johannes Stigler from Ludwig-Maximilians-Universität München. The study was supported by the LMU-NYU Research Cooperation Program.
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